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1
St-Pierre, M. V., G. A. Kullak-Ublick, B. Hagenbuch y P. J. Meier. "Transport of bile acids in hepatic and non-hepatic tissues". Journal of Experimental Biology 204, n.º 10 (15 de mayo de 2001): 1673–86. http://dx.doi.org/10.1242/jeb.204.10.1673.
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Bile acids are steroidal amphipathic molecules derived from the catabolism of cholesterol. They modulate bile flow and lipid secretion, are essential for the absorption of dietary fats and vitamins, and have been implicated in the regulation of all the key enzymes involved in cholesterol homeostasis. Bile acids recirculate through the liver, bile ducts, small intestine and portal vein to form an enterohepatic circuit. They exist as anions at physiological pH and, consequently, require a carrier for transport across the membranes of the enterohepatic tissues. Individual bile acid carriers have now been cloned from several species. Na(+)-dependent transporters that mediate uptake into hepatocytes and reabsorption from the intestine and biliary epithelium and an ATP-dependent transporter that pumps bile acids into bile comprise the classes of transporter that are specific for bile acids. In addition, at least four human and five rat genes that code for Na(+)-independent organic anion carriers with broad multi-substrate specificities that include bile acids have been discovered. Studies concerning the regulation of these carriers have permitted identification of molecular signals that dictate eventual changes in the uptake or excretion of bile acids, which in turn have profound physiological implications. This overview summarizes and compares all known bile acid transporters and highlights findings that have identified diseases linked to molecular defects in these carriers. Recent advances that have fostered a more complete appreciation for the elaborate disposition of bile acids in humans are emphasized.
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Garzel, Brandy, Lei Zhang, Shiew-Mei Huang y Hongbing Wang. "A Change in Bile Flow: Looking Beyond Transporter Inhibition in the Development of Drug-induced Cholestasis". Current Drug Metabolism 20, n.º 8 (24 de septiembre de 2019): 621–32. http://dx.doi.org/10.2174/1389200220666190709170256.
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Background:Drug-induced Liver Injury (DILI) has received increasing attention over the past decades, as it represents the leading cause of drug failure and attrition. One of the most prevalent and severe forms of DILI involves the toxic accumulation of bile acids in the liver, known as Drug-induced Cholestasis (DIC). Traditionally, DIC is studied by exploring the inhibition of hepatic transporters such as Bile Salt Export Pump (BSEP) and multidrug resistance-associated proteins, predominantly through vesicular transport assays. Although this approach has identified numerous drugs that alter bile flow, many DIC drugs do not demonstrate prototypical transporter inhibition, but rather are associated with alternative mechanisms.Methods:We undertook a focused literature search on DIC and biliary transporters and analyzed peer-reviewed publications over the past two decades or so.Results:We have summarized the current perception regarding DIC, biliary transporters, and transcriptional regulation of bile acid homeostasis. A growing body of literature aimed to identify alternative mechanisms in the development of DIC has been evaluated. This review also highlights current in vitro approaches used for prediction of DIC.Conclusion:Efforts have continued to focus on BSEP, as it is the primary route for hepatic biliary clearance. In addition to inhibition, drug-induced BSEP repression or the combination of these two has emerged as important alternative mechanisms leading to DIC. Furthermore, there has been an evolution in the approaches to studying DIC including 3D cell cultures and computational modeling.
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Roma, Marcelo G., Ismael R. Barosso, Gisel S. Miszczuk, Fernando A. Crocenzi y Enrique J. Sánchez Pozzi. "Dynamic Localization of Hepatocellular Transporters: Role in Biliary Excretion and Impairment in Cholestasis". Current Medicinal Chemistry 26, n.º 7 (14 de mayo de 2019): 1113–54. http://dx.doi.org/10.2174/0929867325666171205153204.
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Bile flow generation is driven by the vectorial transfer of osmotically active compounds from sinusoidal blood into a confined space, the bile canaliculus. Hence, localization of hepatocellular transporters relevant to bile formation is crucial for bile secretion. Hepatocellular transporters are localized either in the plasma membrane or in recycling endosomes, from where they can be relocated to the plasma membrane on demand, or endocytosed when the demand decreases. The balance between endocytic internalization/ exocytic targeting to/from this recycling compartment is therefore the main determinant of the hepatic capability to generate bile, and to dispose endo- and xenobiotics. Furthermore, the exacerbated endocytic internalization is a common pathomechanisms in both experimental and human cholestasis; this results in bile secretory failure and, eventually, posttranslational transporter downregulation by increased degradation. This review summarizes the proposed structural mechanisms accounting for this pathological condition (e.g., alteration of function, localization or expression of F-actin or F-actin/transporter cross-linking proteins, and switch to membrane microdomains where they can be readily endocytosed), and the mediators implicated (e.g., triggering of “cholestatic” signaling transduction pathways). Lastly, we discussed the efficacy to counteract the cholestatic failure induced by transporter internalization of a number of therapeutic experimental approaches based upon the use of compounds that trigger exocytic targetting of canalicular transporters (e.g., cAMP, tauroursodeoxycholate). This therapeutics may complement treatments aimed to transcriptionally improve transporter expression, by affording proper localization and membrane stability to the de novo synthesized transporters.
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Roberts, Michael S., Xin Liu, Yuhong Zou, Gerhard A. Siebert, Ping Chang, Michael W. Whitehouse, Linda Fletcher y Darrell H. G. Crawford. "Effect of adjuvant-induced systemic inflammation in rats on hepatic disposition kinetics of taurocholate". American Journal of Physiology-Gastrointestinal and Liver Physiology 300, n.º 1 (enero de 2011): G130—G136. http://dx.doi.org/10.1152/ajpgi.00162.2010.
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It has been reported that the adjuvant-induced inflammation could affect drug metabolism in liver. Here we further investigated the effect of inflammation on drug transport in liver using taurocholate as a model drug. The hepatic disposition kinetics of [3H]taurocholate in perfused normal and adjuvant-treated rat livers were investigated by the multiple indicator dilution technique and data were analyzed by a previously reported hepatobiliary taurocholate transport model. Real-time RT-PCR was also performed to determine the mRNA expression of liver bile salt transporters in normal and diseased livers. The uptake and biliary excretion of taurocholate were impaired in the adjuvant-treated rats as shown by decreased influx rate constant kin (0.65 ± 0.09 vs. 2.12 ± 0.30) and elimination rate constant kbe (0.09 ± 0.02 vs. 0.17 ± 0.04) compared with control rat group, whereas the efflux rate constant kout was greatly increased (0.07 ± 0.02 vs. 0.02 ± 0.01). The changes of mRNA expression of liver bile salt transporters were found in adjuvant-treated rats. Hepatic taurocholate extraction ratio in adjuvant-treated rats (0.86 ± 0.05, n = 6) was significantly reduced compared with 0.93 ± 0.05 ( n = 6) in normal rats. Hepatic extraction was well correlated with altered hepatic ATP content ( r2 = 0.90). In conclusion, systemic inflammation greatly affects hepatic ATP content/production and associated transporter activities and causes an impairment of transporter-mediated solute trafficking and pharmacokinetics.
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Gooijert, K. E. R., R. Havinga, H. Wolters, R. Wang, V. Ling, S. Tazuma y H. J. Verkade. "The mechanism of increased biliary lipid secretion in mice with genetic inactivation of bile salt export pump". American Journal of Physiology-Gastrointestinal and Liver Physiology 308, n.º 5 (1 de marzo de 2015): G450—G457. http://dx.doi.org/10.1152/ajpgi.00391.2014.
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Human bile salt export pump ( BSEP) mutations underlie progressive familial intrahepatic cholestasis type 2 (PFIC2). In the PFIC2 animal model, Bsep−/−mice, biliary secretion of bile salts (BS) is decreased, but that of phospholipids (PL) and cholesterol (CH) is increased. Under physiological conditions, the biliary secretion of PL and CH is positively related (“coupled”) to that of BS. We aimed to elucidate the mechanism of increased biliary lipid secretion in Bsep−/−mice. The secretion of the BS tauro-β-muricholic acid (TβMCA) is relatively preserved in Bsep−/−mice. We infused Bsep−/−and Bsep+/+(control) mice with TβMCA in stepwise increasing dosages (150–600 nmol/min) and determined biliary bile flow, BS, PL, and CH secretion. mRNA and protein expression of relevant canalicular transporters was analyzed in livers from noninfused Bsep−/−and control mice. TβMCA infusion increased BS secretion in both Bsep−/−and control mice. The secreted PL or CH amount per BS, i.e., the “coupling,” was continuously two- to threefold higher in Bsep−/−mice ( P < 0.05). Hepatic mRNA expression of canalicular lipid transporters Mdr2, Abcg5, and Abcg8 was 45–55% higher in Bsep−/−mice (Abcg5; P < 0.05), as was canalicular Mdr2 and Abcg5 protein expression. Potential other explanations for the increased coupling of the biliary secretion of PL and CH to that of BS in Bsep−/−mice could be excluded. We conclude that the mechanism of increased biliary lipid secretion in Bsep−/−mice is based on increased expression of the responsible canalicular transporter proteins.
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Parasrampuria, Ridhi, Imam H. Shaik y Reza Mehvar. "Effects of In Vivo Hepatic Ischemia-Reperfusion Injury on the Hepatobiliary Disposition of Rhodamine 123 and its Metabolites in Isolated Perfused Rat Livers". Journal of Pharmacy & Pharmaceutical Sciences 15, n.º 2 (30 de abril de 2012): 318. http://dx.doi.org/10.18433/j3ms40.
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Purpose. A few studies have shown that normothermic hepatic ischemia-reperfusion (IR) injury may affect the mRNA and/or protein levels of canalicular transporters P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (Mrp2). However, the effects of the injury on the functions of these canalicular transporters with respect to the biliary excretion of drugs remain largely unknown. Therefore, the purpose of this study was to investigate the effects of warm hepatic IR on the hepatobiliary disposition of rhodamine 123 (RH-123), a P-gp substrate, and its glucuronidated metabolite (RH-Glu), an Mrp2 substrate, in rats. Methods. Twenty four or 72 h following a 60-min partial ischemia or sham operation in rats, livers were isolated and perfused ex vivo with a constant concentration (~100 ng/mL) of RH-123. The concentration of RH-123 and its glucuronidated (RH-Glu) and deacylated (RH-110) metabolites were determined in the outlet perfusate, bile, and the liver tissue using HPLC, and relevant pharmacokinetic parameters were estimated. Results. Twenty-four-h IR caused a significant reduction in the hepatic extraction ratio of RH-123 (IR: 0.857 ± 0.078; Sham: 0.980 ± 0.017) and the biliary recovery of the parent drug and RH-Glu by 43% and 44%, respectively. The reductions in the biliary recovery were associated with significant reductions in the apparent biliary clearance of RH-123 and RH-Glu. Mass balance data showed that the formation of the glucuronidated or deacylated metabolite was not significantly affected by the 24-h IR injury. In contrast to the 24-h IR, the injury did not have any effect on the hepatobiliary disposition of RH-123 or its metabolites following 72 h of reperfusion. Conclusions. It is concluded that the pharmacokinetics of drugs that are subject to biliary excretion by the canalicular P-gp and Mrp2 transporters may be altered shortly after hepatic IR injury.
This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
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Kawase, Atsushi, Ayumi Handa y Masahiro Iwaki. "EFFECTS OF FASTING ON PRAVASTATIN DISPOSITION IN PERFUSED RAT LIVER". International Journal of Pharmacy and Pharmaceutical Sciences 8, n.º 12 (1 de diciembre de 2016): 130. http://dx.doi.org/10.22159/ijpps.2016v8i12.14950.
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<p><strong>Objective: </strong>Various nutrients such as glucose and cholesterol affect the expression of hepatic transporters. Although the pharmacokinetics of some drugs is affected by fasting, the fasting effects on drug hepatic disposition via alterations in transporters are unclear. Organic anion-transporting polypeptides and multidrug resistance-associated protein 2 (Mrp2/Abcc2) expressed in the liver are involved in hepatic disposition of pravastatin.</p><p><strong>Methods: </strong>An <em>in situ</em> perfused rat liver system was established. The mRNA and protein levels of transporters in the liver were examined by real-time reverse transcription PCR and western blotting. The localization of Mrp2 in hepatocytes was determined by immunostaining.</p><p><strong>Results: </strong>Pravastatin was rapidly eliminated from the perfusate. The cumulative biliary excretion amounts of pravastatin in fasting rats were significantly lower from 10 min compared with control. In fasting rats, the area under the plasma concentration-time curve (<em>AUC</em>)<sub>0‒∞</sub> of pravastatin in the perfusate was significantly decreased, and hepatic clearance (<em>CL<sub>h</sub></em>) and hepatic corrected clearance (<em>CL<sub>cor</sub></em>) were significantly increased. The biliary clearance (<em>CL<sub>bile</sub></em>) in fasting rats tended to decrease compared with that in control rats. Protein expression levels of transporters were unchanged after fasting. Confocal microscopy revealed a disruption of Mrp2 and ZO-1 colocalization in the liver of fasting rats.</p><p><strong>Conclusion: </strong>The biliary excretion of pravastatin was inhibited by fasting via decreased Mrp2 localization on the canalicular membrane.</p>
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Csanaky, Iván L., Lauren M. Aleksunes, Yuji Tanaka y Curtis D. Klaassen. "Role of hepatic transporters in prevention of bile acid toxicity after partial hepatectomy in mice". American Journal of Physiology-Gastrointestinal and Liver Physiology 297, n.º 3 (septiembre de 2009): G419—G433. http://dx.doi.org/10.1152/ajpgi.90728.2008.
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The enterohepatic recirculation of bile acids (BAs) is important in several physiological processes. Although there has been considerable research on liver regeneration after two-thirds partial hepatectomy (PHx), little is known about how the liver protects itself against BA toxicity during regeneration. In this study, various BAs in plasma and liver, the composition of micelle-forming bile constituents, as well as gene expression of the main hepatobiliary transporters were quantified in sham-operated and PHx mice 24 and 48 h after surgery. PHx did not influence the hepatic concentrations of taurine-conjugated BAs (T-BA) but increased the concentration of glycine-conjugated (G-BA) and unconjugated BAs. Total BA excretion (μg·min−1·g liver wt−1) increased 2.4-fold and was accompanied by a 55% increase in bile flow after PHx. The plasma concentrations of T-BAs (402-fold), G-BAs (17-fold), and unconjugated BAs (500-fold) increased. The mRNA and protein levels of the BA uptake transporter Ntcp were unchanged after PHx, whereas the canalicular Bsep protein increased twofold at 48 h. The basolateral efflux transporter Mrp3 was induced at the mRNA (2.6-fold) and protein (3.1-fold) levels after PHx, which may contribute to elevated plasma BA and bilirubin levels. Biliary phospholipid excretion was nearly doubled in PHx mice, most likely owing to increased mRNA expression of the phospholipid transporter, Mdr2. In conclusion, the remnant liver after PHx excretes 2.5-fold more BAs and three times more phospholipids per gram liver than the sham-operated mouse liver. Upregulation of phospholipid transport may be important in protecting the biliary tract from BA toxicity during PHx.
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Govindarajan, Rajgopal, Christopher J. Endres, Dale Whittington, Edward LeCluyse, Marçal Pastor-Anglada, Chung-Ming Tse y Jashvant D. Unadkat. "Expression and hepatobiliary transport characteristics of the concentrative and equilibrative nucleoside transporters in sandwich-cultured human hepatocytes". American Journal of Physiology-Gastrointestinal and Liver Physiology 295, n.º 3 (septiembre de 2008): G570—G580. http://dx.doi.org/10.1152/ajpgi.00542.2007.
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We previously reported that both the concentrative (hCNT) and equilibrative (hENT) nucleoside transporters are expressed in the human liver ( 21 ). Here we report a study that investigated the expression of these transporters (transcripts and proteins) and their role in the hepatobiliary transport of nucleosides/nucleoside drugs using sandwich-cultured human hepatocytes. In the hepatic tissue, the rank order of the mRNA expression of the transporters was hCNT1 ≈ hENT1 > hENT2 ≈ hCNT2 > hCNT3. In sandwich-cultured hepatocytes, the mRNA expression of hCNT2 and hENT2 was comparable to that in hepatic tissue, whereas the expression of corresponding transporters in the two-dimensional hepatocyte cultures was lower. Colocalization studies demonstrated predominant localization of these transporters at the sinusoidal membrane and of hENT1, hCNT1, and hCNT2 at the canalicular membrane. In the sandwich-cultured hepatocytes, ENTs were the major contributors to the transport of thymidine (hENT1, 63%; hENT2, 23%) or guanosine (hENT1, 53%; hENT2, 24%) into the hepatocytes followed by hCNT1 (10%) for thymidine or hCNT2 (23%) for guanosine. Although ribavirin was predominately transported (89%) into the hepatocytes by hENT1, fialuridine (FIAU) was transported by both hENT1 (30%) and hCNTs (61%). The extensively metabolized natural nucleosides were not effluxed into the bile, whereas significant biliary-efflux was observed of FIAU (19%), ribavirin (30%), and formycin B (35%). We conclude that the hepatic activity of hENT1 and hCNT1/2 transporters will determine the in vivo hepatic distribution and therefore the efficacy and/or toxicity of nucleoside drugs used to treat hepatic diseases.
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Kaddoumi, Amal y Loqman A. Mohamed. "Tacrine Sinusoidal Uptake and Biliary Excretion in Sandwich-Cultured Primary Rat Hepatocytes". Journal of Pharmacy & Pharmaceutical Sciences 17, n.º 3 (3 de septiembre de 2014): 427. http://dx.doi.org/10.18433/j3801t.
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PURPOSE. The knowledge of hepatic disposition kinetics of tacrine, a first cholinesterase inhibitor was approved by FDA for the treatment of Alzheimer’s disease (AD), would help to understand its hepatotoxicity, its therapeutic effect, and improve the management of patients with AD. The current study aims to characterize tacrine hepatic transport kinetics and study the role of organic cation transporters (OCTs), P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP2) in tacrine sinusoidal uptake and biliary excretion. METHODS. Modulation of tacrine hepatic uptake and efflux, biliary excretion index (BEI%), were performed in sandwich-cultured primary rat hepatocytes (SCHs) using transporters inhibitors. Conformation of the integrity of SCHs model was established by capturing images with light-contrast and fluorescence microscopy. RESULTS. Tacrine uptake in SCHs was carrier-mediated process and saturable with apparent Km of 31.5±9.6 µM and Vmax of 908±72 pmol/min/mg protein. Tetraethyl ammonium (TEA), cimetidine and verapamil significantly reduced tacrine uptake with more pronounced effect observed with verapamil which caused 3-fold reduction in tacrine uptake, indicating role for OCTs. Tacrine has a biliary excretion in SCHs with maximum BEI% value of 22.9±1.9% at 10 min of incubation. Addition of MK571 and valspodar decreased the BEI% of tacrine by 40 and 60% suggesting roles for canalicular MRP2 and P-gp, respectively. CONCLUSIONS. Our results show that in addition to metabolism, tacrine hepatic disposition is carrier-mediated process mediated by sinusoidal OCTs, and canalicular MRP2 and P-gp.This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
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Hinchman, Cheri A., James F. Rebbeor y Nazzareno Ballatori. "Efficient hepatic uptake and concentrative biliary excretion of a mercapturic acid". American Journal of Physiology-Gastrointestinal and Liver Physiology 275, n.º 4 (1 de octubre de 1998): G612—G619. http://dx.doi.org/10.1152/ajpgi.1998.275.4.g612.
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The role of the liver in the disposition of circulating mercapturic acids was examined in anesthetized rats and in the isolated perfused rat liver using S-2,4-dinitrophenyl- N-acetylcysteine (DNP-NAC) as the model compound. When DNP-NAC was infused into the jugular vein (150 or 600 nmol over 60 min) it was rapidly and nearly quantitatively excreted as DNP-NAC into bile (42–36% of the dose) and urine (48–62% of dose). Some minor metabolites were detected in bile (<4%), with the major metabolite coeluting on HPLC with the DNP conjugate of glutathione (DNP-SG). Isolated rat livers perfused single pass with 3 μM DNP-NAC removed 72 ± 9% of this mercapturic acid from perfusate. This rapid DNP-NAC uptake was unaffected by sodium omission, or byl-cysteine,l-glutamate,l-cystine, or N-acetylated amino acids, but was decreased by inhibitors of hepatic sinusoidal organic anion transporters (oatp), indicating that DNP-NAC is a substrate for these transporters. The DNP-NAC removed from perfusate was promptly excreted into bile, eliciting a dose-dependent choleresis. DNP-NAC itself constituted ∼75% of the total dose recovered in bile, reaching a concentration of 9 mM when livers were perfused in a recirculating mode with an initial DNP-NAC concentration of 250 μM. Other biliary metabolites included DNP-SG, DNP-cysteinylglycine, and DNP-cysteine. DNP-SG was likely formed by a spontaneous retro-Michael reaction between glutathione and DNP-NAC. Subsequent degradation of DNP-SG by biliary γ-glutamyltranspeptidase and dipeptidase activities accounts for the cysteinylglycine and cysteine conjugates, respectively. These findings indicate the presence of efficient hepatic mechanisms for sinusoidal uptake and biliary excretion of circulating mercapturic acids in rat liver and demonstrate that the liver plays a role in their whole body elimination.
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Howell, Lawrence, Rosalind E. Jenkins, Stephen Lynch, Carrie Duckworth, B. Kevin Park y Christopher Goldring. "Proteomic profiling of murine biliary-derived hepatic organoids and their capacity for drug disposition, bioactivation and detoxification". Archives of Toxicology 95, n.º 7 (29 de mayo de 2021): 2413–30. http://dx.doi.org/10.1007/s00204-021-03075-3.
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AbstractHepatic organoids are a recent innovation in in vitro modeling. Initial studies suggest that organoids better recapitulate the liver phenotype in vitro compared to pre-existing proliferative cell models. However, their potential for drug metabolism and detoxification remains poorly characterized, and their global proteome has yet to be compared to their tissue of origin. This analysis is urgently needed to determine what gain-of-function this new model may represent for modeling the physiological and toxicological response of the liver to xenobiotics. Global proteomic profiling of undifferentiated and differentiated hepatic murine organoids and donor-matched livers was, therefore, performed to assess both their similarity to liver tissue, and the expression of drug-metabolizing enzymes and transporters. This analysis quantified 4405 proteins across all sample types. Data are available via ProteomeXchange (PXD017986). Differentiation of organoids significantly increased the expression of multiple cytochrome P450, phase II enzymes, liver biomarkers and hepatic transporters. While the final phenotype of differentiated organoids is distinct from liver tissue, the organoids contain multiple drug metabolizing and transporter proteins necessary for liver function and drug metabolism, such as cytochrome P450 3A, glutathione-S-transferase alpha and multidrug resistance protein 1A. Indeed, the differentiated organoids were shown to exhibit increased sensitivity to midazolam (10–1000 µM) and irinotecan (1–100 µM), when compared to the undifferentiated organoids. The predicted reduced activity of HNF4A and a resulting dysregulation of RNA polymerase II may explain the partial differentiation of the organoids. Although further experimentation, optimization and characterization is needed relative to pre-existing models to fully contextualize their use as an in vitro model of drug-induced liver injury, hepatic organoids represent an attractive novel model of the response of the liver to xenobiotics. The current study also highlights the utility of global proteomic analyses for rapid and accurate evaluation of organoid-based test systems.
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Duan, Li-Ping, Helen H. Wang, Akira Ohashi y David Q. H. Wang. "Role of intestinal sterol transporters Abcg5, Abcg8, and Npc1l1 in cholesterol absorption in mice: gender and age effects". American Journal of Physiology-Gastrointestinal and Liver Physiology 290, n.º 2 (febrero de 2006): G269—G276. http://dx.doi.org/10.1152/ajpgi.00172.2005.
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Recent studies have indicated that intestinal cholesterol absorption is a multistep process, which is regulated by multiple genes at the enterocyte level. However, the molecular mechanisms whereby there are gender differences in intestinal cholesterol absorption efficiency and the efficiency of cholesterol absorption increases with age have not yet been fully understood. To explore whether aging increases cholesterol absorption via intestinal sterol transporters, we studied the higher cholesterol-absorbing C57L/J vs. the lower cholesterol-absorbing AKR/J mice at 8 (young adult), 36 (older adult), and 50 (aged) wk of age. To test the hypothesis that estrogen receptor (ER )α plays an important regulatory role in cholesterol absorption, we investigated the gonadectomized mice of both genders treated with 17β-estradiol-releasing pellets at 0, 3, or 6 μg/day and antiestrogenic ICI 182,780 at 125 μg/day. We found that hepatic outputs of biliary cholesterol were significantly increased with age and in response to high levels of estrogen. Aging significantly enhances cholesterol absorption by suppressing expression of the jejunal and ileal sterol efflux transporters [ATP-binding cassette ( Abc) g5 and Abcg8] and upregulating expression of the putative duodenal and jejunal sterol influx transporter Npc1l1. Estrogen significantly augmented cholesterol absorption mostly due to an upregulated expression of intestinal Npc1l1, Abcg5, and Abcg8 via the intestinal ERα pathway, which can be fully abolished by the antagonist. We conclude that ERα activated by estrogen and aging enhances cholesterol absorption by increasing biliary lipid output and mediating intestinal sterol transporters favoring influx of intraluminal cholesterol molecules across the apical membrane of the enterocyte.
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Trauner, Michael y James L. Boyer. "Bile Salt Transporters: Molecular Characterization, Function, and Regulation". Physiological Reviews 83, n.º 2 (1 de abril de 2003): 633–71. http://dx.doi.org/10.1152/physrev.00027.2002.
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Molecular medicine has led to rapid advances in the characterization of hepatobiliary transport systems that determine the uptake and excretion of bile salts and other biliary constituents in the liver and extrahepatic tissues. The bile salt pool undergoes an enterohepatic circulation that is regulated by distinct bile salt transport proteins, including the canalicular bile salt export pump BSEP (ABCB11), the ileal Na+-dependent bile salt transporter ISBT (SLC10A2), and the hepatic sinusoidal Na+- taurocholate cotransporting polypeptide NTCP (SLC10A1). Other bile salt transporters include the organic anion transporting polypeptides OATPs (SLC21A) and the multidrug resistance-associated proteins 2 and 3 MRP2,3 (ABCC2,3). Bile salt transporters are also present in cholangiocytes, the renal proximal tubule, and the placenta. Expression of these transport proteins is regulated by both transcriptional and posttranscriptional events, with the former involving nuclear hormone receptors where bile salts function as specific ligands. During bile secretory failure (cholestasis), bile salt transport proteins undergo adaptive responses that serve to protect the liver from bile salt retention and which facilitate extrahepatic routes of bile salt excretion. This review is a comprehensive summary of current knowledge of the molecular characterization, function, and regulation of bile salt transporters in normal physiology and in cholestatic liver disease and liver regeneration.
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Weerachayaphorn, Jittima, Albert Mennone, Carol J. Soroka, Kathy Harry, Lee R. Hagey, Thomas W. Kensler y James L. Boyer. "Nuclear factor-E2-related factor 2 is a major determinant of bile acid homeostasis in the liver and intestine". American Journal of Physiology-Gastrointestinal and Liver Physiology 302, n.º 9 (1 de mayo de 2012): G925—G936. http://dx.doi.org/10.1152/ajpgi.00263.2011.
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The transcription factor nuclear factor-E2-related factor 2 (Nrf2) is a key regulator for induction of hepatic detoxification and antioxidant mechanisms, as well as for certain hepatobiliary transporters. To examine the role of Nrf2 in bile acid homeostasis and cholestasis, we assessed the determinants of bile secretion and bile acid synthesis and transport before and after bile duct ligation (BDL) in Nrf2−/− mice. Our findings indicate reduced rates of biliary bile acid and GSH excretion, higher levels of intrahepatic bile acids, and decreased expression of regulators of bile acid synthesis, Cyp7a1 and Cyp8b1, in Nrf2−/− compared with wild-type control mice. The mRNA expression of the bile acid transporters bile salt export pump ( Bsep) and organic solute transporter ( Ostα) were increased in the face of impaired expression of the multidrug resistance-associated proteins Mrp3 and Mrp4. Deletion of Nrf2 also decreased ileal apical sodium-dependent bile acid transporter ( Asbt) expression, leading to reduced bile acid reabsorption and increased loss of bile acid in feces. Finally, when cholestasis is induced by BDL, liver injury was not different from that in wild-type BDL mice. These Nrf2−/− mice also had increased pregnane X receptor ( Pxr) and Cyp3a11 mRNA expression in association with enhanced hepatic bile acid hydroxylation. In conclusion, this study finds that Nrf2 plays a major role in the regulation of bile acid homeostasis in the liver and intestine. Deletion of Nrf2 results in a cholestatic phenotype but does not augment liver injury following BDL.
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Macias, Rocio I. R., Carlos Hierro, Susana Cuesta de Juan, Felipe Jimenez, Francisco Gonzalez-San Martin y Jose J. G. Marin. "Hepatic expression of sodium-dependent vitamin C transporters: ontogeny, subtissular distribution and effect of chronic liver diseases". British Journal of Nutrition 106, n.º 12 (1 de julio de 2011): 1814–25. http://dx.doi.org/10.1017/s0007114511002273.
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Ascorbic acid uptake is a key step in determining the overall bioactivity of this vitamin. Expression of Na-dependent vitamin C transporters (SVCT; SLC23A1 and SLC23A2) during long-term oxidative stress occurring in several chronic liver diseases may determine the antioxidant defence in this organ. In patients with hepatocellular cholestasis, primary biliary cirrhosis, haemochromatosis and non-alcoholic steatohepatitis, using real-time RT-PCR, an enhanced hepatic expression of both SLC23A1 and SLC23A2, but not other organic anions transporters, such as OATP1A2, OATP1B1 and OATP1B3, was found. To further investigate these findings, we used secondary biliary cirrhosis induced in rats by long-term biliary obstruction as a model of chronic liver disease accompanied by oxidative stress because of bile acid accumulation. In control rat liver, expression of Slc23a1 was low at birth, increased progressively up to adulthood and decreased in senescence, whereas expression of Slc23a2 did not change significantly after birth. In 8-week-old rats, immunohistochemistry and confocal microscopy studies revealed the expression in hepatocytes and bile duct cells of mainly Slc23a1, whereas both Slc23a1 and Slc23a2 were expressed in endothelial, stellate and Kupffer cells. In adult rats, when obstructive cholestasis was maintained for 8 weeks, a significant up-regulation of Slc23a2 accompanied by a down-regulation of Slc23a1 was found. In sum, there is a selective cell-type distribution of SVCT in the liver tissue, which, in addition to differential control in the expression of both isoforms, may play a role in the ability of different liver cell types to take up vitamin C under physiological and pathological conditions.
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Thomas, Levin, Sonal Sekhar Miraj, Mallayasamy Surulivelrajan, Muralidhar Varma, Chidananda S. V. Sanju y Mahadev Rao. "Influence of Single Nucleotide Polymorphisms on Rifampin Pharmacokinetics in Tuberculosis Patients". Antibiotics 9, n.º 6 (8 de junio de 2020): 307. http://dx.doi.org/10.3390/antibiotics9060307.
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Rifampin (RF) is metabolized in the liver into an active metabolite 25-desacetylrifampin and excreted almost equally via biliary and renal routes. Various influx and efflux transporters influence RF disposition during hepatic uptake and biliary excretion. Evidence has also shown that Vitamin D deficiency (VDD) and Vitamin D receptor (VDR) polymorphisms are associated with tuberculosis (TB). Hence, genetic polymorphisms of metabolizing enzymes, drug transporters and/or their transcriptional regulators and VDR and its pathway regulators may affect the pharmacokinetics of RF. In this narrative review, we aim to identify literature that has explored the influence of single nucleotide polymorphisms (SNPs) of genes encoding drug transporters and their transcriptional regulators (SLCO1B1, ABCB1, PXR and CAR), metabolizing enzymes (CES1, CES2 and AADAC) and VDR and its pathway regulators (VDR, CYP27B1 and CYP24A1) on plasma RF concentrations in TB patients on antitubercular therapy. Available reports to date have shown that there is a lack of any association of ABCB1, PXR, CAR, CES1 and AADAC genetic variants with plasma concentrations of RF. Further evidence is required from a more comprehensive exploration of the association of SLCO1B1, CES2 and Vitamin D pathway gene variants with RF pharmacokinetics in distinct ethnic groups and a larger population to reach conclusive information.
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Wang, Renxue, Lin Liu, Jonathan A. Sheps, Dana Forrest, Alan F. Hofmann, Lee R. Hagey y Victor Ling. "Defective canalicular transport and toxicity of dietary ursodeoxycholic acid in the abcb11−/− mouse: transport and gene expression studies". American Journal of Physiology-Gastrointestinal and Liver Physiology 305, n.º 4 (15 de agosto de 2013): G286—G294. http://dx.doi.org/10.1152/ajpgi.00082.2013.
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The bile salt export pump (BSEP), encoded by the abcb11 gene, is the major canalicular transporter of bile acids from the hepatocyte. BSEP malfunction in humans causes bile acid retention and progressive liver injury, ultimately leading to end-stage liver failure. The natural, hydrophilic, bile acid ursodeoxycholic acid (UDCA) is efficacious in the treatment of cholestatic conditions, such as primary biliary cirrhosis and cholestasis of pregnancy. The beneficial effects of UDCA include promoting bile flow, reducing hepatic inflammation, preventing apoptosis, and maintaining mitochondrial integrity in hepatocytes. However, the role of BSEP in mediating UDCA efficacy is not known. Here, we used abcb11 knockout mice ( abcb11 −/−) to test the effects of acute and chronic UDCA administration on biliary secretion, bile acid composition, liver histology, and liver gene expression. Acutely infused UDCA, or its taurine conjugate (TUDC), was taken up by the liver but retained, with negligible biliary output, in abcb11−/− mice. Feeding UDCA to abcb11−/− mice led to weight loss, retention of bile acids, elevated liver enzymes, and histological damage to the liver. Semiquantitative RT-PCR showed that genes encoding Mdr1a and Mdr1b (canalicular) as well as Mrp4 (basolateral) transporters were upregulated in abcb11−/− mice. We concluded that infusion of UDCA and TUDC failed to induce bile flow in abcb11−/− mice. UDCA fed to abcb11−/− mice caused liver damage and the appearance of biliary tetra- and penta-hydroxy bile acids. Supplementation with UDCA in the absence of Bsep caused adverse effects in abcb11−/− mice.
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Bertolotti, M., C. Gabbi, C. Anzivino, E. Tagliafico, L. Carulli, A. Rossi, P. Loria y N. Carulli. "[300] HEPATIC EXPRESSION OF NUCLEAR RECEPTORS AND BILIARY TRANSPORTERS IN HUMAN CHOLESTEROL GALLSTONE DISEASE". Journal of Hepatology 46 (abril de 2007): S119. http://dx.doi.org/10.1016/s0168-8278(07)61898-4.
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Hidemura, Kazuhiko, Ying Lan Zhao, Katsuki Ito, Akimasa Nakao, Yasuaki Tatsumi, Hiroaki Kanazawa, Kenzo Takagi, Michio Ohta y Takaaki Hasegawa. "Shiga-Like Toxin II Impairs Hepatobiliary Transport of Doxorubicin in Rats by Down-Regulation of Hepatic P Glycoprotein and Multidrug Resistance-Associated Protein Mrp2". Antimicrobial Agents and Chemotherapy 47, n.º 5 (mayo de 2003): 1636–42. http://dx.doi.org/10.1128/aac.47.5.1636-1642.2003.
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ABSTRACT We investigated the effect of Shiga-like toxin II (SLT-II), derived from Escherichia coli O157:H7, on the hepatobiliary excretion of doxorubicin, a substrate for P glycoprotein and the multidrug resistance-associated protein Mrp2, and on the expression of P glycoprotein and Mrp2 in rats. Histopathological examination did not show any liver injury in SLT-II-treated rats. A significant delay in the disappearance of doxorubicin from plasma after its intravenous administration (5 mg/kg of body weight) was observed in rats treated 24 h earlier with SLT-II (2 μg/animal). When rats received an infusion of doxorubicin (2.6 μg/min) 24 h after intravenous injection of SLT-II, the steady-state concentration of doxorubicin in plasma increased and the bile flow decreased, whereas the concentration in liver did not alter. SLT-II significantly increased the unbound fraction of doxorubicin in plasma but did not alter the concentration in liver tissue. SLT-II significantly decreased the biliary excretion rate and biliary clearance of doxorubicin based on the total concentration and concentration of the unbound fraction in plasma and liver. Western blot analysis revealed that SLT-II down-regulated P glycoprotein and Mrp2 in the liver, which could explain the observed decrease in the biliary excretion of doxorubicin by SLT-II. A tumor necrosis factor alpha (TNF-α) production inhibitor, pentoxifylline, could not protect SLT-II-induced decreases in the biliary clearance of doxorubicin and down-regulation of both transporters. It is unlikely that TNF-α plays a major role in the SLT-II-induced decrease in the hepatobiliary transport of doxorubicin and the down-regulation of both transporters.
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Michael, Michael, Mick Thompson, Rod J. Hicks, Paul L. Mitchell, Andrew Ellis, Alvin D. Milner, Julia Di Iulio et al. "Relationship of Hepatic Functional Imaging to Irinotecan Pharmacokinetics and Genetic Parameters of Drug Elimination". Journal of Clinical Oncology 24, n.º 26 (10 de septiembre de 2006): 4228–35. http://dx.doi.org/10.1200/jco.2005.04.8496.
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Purpose The marked variability of irinotecan (Ir) clearance warrants individualized dosing based on hepatic drug handling. The aims of this trial were to identify parameters from functional hepatic nuclear imaging (HNI) that correlate with (1) Ir pharmacology, and (2) single-nucleotide polymorphisms (SNPs) for the ABCB1 (P-glycoprotein) and UGT-1A1 genes, known to influence Ir handling. Methods Patients underwent genotyping for ABCB1 SNPs and UTUGT-1A1*28 carriage and HNI with 99mTc-DIDA (acetanilidoiminodiacetic acid)/ 99mTc-DISIDA (disofenin) and MIBI (99mTc-sestamibi) scans, probes for biliary transport proteins ABCC1 and -2, and ABCB1 function. HNI data were analyzed by noncompartmental and deconvolutional analysis to provide hepatic extraction and biliary excretion parameters. Patients received Ir, fluorouracil, and folinic acid using a weekly ×2, every-3-weeks schedule. Plasma was taken for Ir and SN-38 analysis on day 1, cycle 1. Results Of the 21 patients accrued, Ir pharmacokinetics data were obtained from 16 patients. 99mTc-DIDA/DISIDA percent retention at 1 hour (1-hour RET) correlated to baseline serum bilirubin (P = .008). Both 99mTc-DIDA/DISIDA and MIBI 1-hour RET correlated with SN-38 area under the curve (AUC; P < .01). On multiple regression analysis, SN-38 AUC = −215 + 18.68 × bilirubin + 4.27 × MIBI 1-hour RET (P = .009, R2 = 44.2%). HNI parameters did not correlate with Ir toxicity or UGT1A1*28 carriage. MIBI excretion was prolonged in patients with the ABCB1 exon 26 TT variant allele relative to wild-type (P = .015). Conclusion Functional imaging of hepatic uptake and excretory pathways may have potential to predict Ir pharmacokinetics. Evaluation of a larger cohort as well as polymorphisms in other biliary transporters and UGT1A1 alleles is warranted.
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Grime, Ken y Stuart W. Paine. "Species Differences in Biliary Clearance and Possible Relevance of Hepatic Uptake and Efflux Transporters Involvement". Drug Metabolism and Disposition 41, n.º 2 (8 de noviembre de 2012): 372–78. http://dx.doi.org/10.1124/dmd.112.049312.
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Maruyama, Hajime, Jiro Ogura, Asuka Fujikawa, Yusuke Terada, Takashi Tsujimoto, Takahiro Koizumi, Kaori Kuwayama, Masaki Kobayashi, Hiroaki Yamaguchi y Ken Iseki. "Intestinal Ischemia-Reperfusion Suppresses Biliary Excretion of Hepatic Organic Anion Transporting Polypeptides Substrate". Journal of Pharmacy & Pharmaceutical Sciences 16, n.º 5 (17 de diciembre de 2013): 722. http://dx.doi.org/10.18433/j3nc8p.
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Purpose. Intestinal ischemia-reperfusion (I/R) causes gut dysfunction and promotes multi-organ failure. The liver and kidney can be affected by multi-organ failure after intestinal I/R. Organic anion transporting polypeptides (OATPs) and organic anion transporters (OATs) are recognized in a broad spectrum from endogenous compounds to xenobiotics, including clinically important drugs. Therefore, it is important for understanding the pharmacokinetics to obtain evidence of alterations in OATPs and OATs expression and transport activities. In the present study, we investigated the expression of rat Oatps and Oats after intestinal I/R. Methods. We used intestinal ischemia-reperfusion (I/R) model rats. Real-time PCR and Western blotting were used to assess mRNA and protein expression levels. Plasma concentration and biliary excretion of sulfobromophthalein (BSP), which is used as a model compound of organic anion drugs, were measured after intravenous administration in intestinal I/R rats. Results. Although Oat1 and Oat3 mRNA levels were not altered in the kidney, Oatp1a1, Oatp1b2 and Oatp2b1 mRNA levels in the liver were significantly decreased at 1-6 h after intestinal I/R. Moreover, Oatp1a1 and Oatp2b1 protein expression levels were decreased at 1 h after intestinal I/R. Plasma concentration of BSP, which is a typical substrate of Oatps, in intestinal I/R rats reperfused 1 h was increased than that in sham-operated rats. Moreover, the area under the concentration-time curve (AUC0-90) in intestinal I/R rats reperfused 1 h was significantly increased than that in sham-operated rats. The total clearance (CLtot) and the biliary clearance (CLbile) in intestinal I/R rats reperfused 1 h were significantly decreased than those in sham-operated rats. Conclusions. Oatp1a1 and Oatp2b1 expression levels are decreased by intestinal I/R. The decreases in these transporters cause alteration of pharmacokinetics of organic anion compound. The newly found influence of intestinal I/R on the expression and function of Oatps may be a key to perform appropriate drug therapy.This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page
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Xiang, Dong, Tao Wu, Cheng-Yang Feng, Xi-Ping Li, Yan-Jiao Xu, Wen-Xi He, Kai Lei, Hong-Jiao Cai, Cheng-Liang Zhang y Dong Liu. "Upregulation of PDZK1 by Calculus Bovis Sativus May Play an Important Role in Restoring Biliary Transport Function in Intrahepatic Cholestasis". Evidence-Based Complementary and Alternative Medicine 2017 (2017): 1–7. http://dx.doi.org/10.1155/2017/1640187.
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Intrahepatic cholestasis is a main cause of hepatic accumulation of bile acids leading to liver injury, fibrosis, and liver failure. Our previous studies proved that Calculus Bovis Sativus (CBS) can restore biliary transport function through upregulating the multidrug resistance-associated protein 2 (MRP2) and breast cancer resistance protein (BCRP) in 17α-ethynylestradiol- (EE-) induced intrahepatic cholestasis rats. The regulation mechanism of CBS on these transporters, however, remains unclear. This study was designed to evaluate the possible relationship between the effect of CBS on transport activities and the regulation of CBS on the expression of PDZK1, a mainly scaffold protein which can regulate MRP2 and BCRP. Intrahepatic cholestasis model was induced in rats with injection of EE for five consecutive days and then the biliary excretion rates and cumulative biliary excretions were measured. The mRNA and protein expression levels of PDZK1 were detected by reverse transcription-quantitative real-time polymerase chain reaction, western blot, and immunohistochemical analysis. When treated with CBS, cumulative biliary excretions and mRNA and protein expressions of PDZK1 were significantly increased in intrahepatic cholestasis rats. This study demonstrated that CBS exerted a beneficial effect on EE-induced intrahepatic cholestasis rats by restoring biliary transport function, which may result from the upregulation of PDZK1 expression.
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Kim, Young Woo, Hee Eun Kang, Myung Gull Lee, Se Jin Hwang, Sang Chan Kim, Chang Ho Lee y Sang Geon Kim. "Liquiritigenin, a flavonoid aglycone from licorice, has a choleretic effect and the ability to induce hepatic transporters and phase-II enzymes". American Journal of Physiology-Gastrointestinal and Liver Physiology 296, n.º 2 (febrero de 2009): G372—G381. http://dx.doi.org/10.1152/ajpgi.90524.2008.
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Liquiritigenin (LQ), an active component of licorice, has an inhibitory effect on LPS-induced inhibitory nitric oxide synthase expression. This study investigated the effects of LQ on choleresis, the expression of hepatic transporters and phase-II enzymes, and fulminant hepatitis. The choleretic effect and the pharmacokinetics of LQ and its glucuronides were monitored in rats. After intravenous administration of LQ, the total area under the plasma concentration-time curve of glucuronyl metabolites was greater than that of LQ in plasma, which accompanied elevations in bile flow rate and biliary excretion of bile acid, glutathione, and bilirubin. The expressions of hepatocellular transporters and phase-II enzymes were assessed by immunoblots, real-time PCR, and immunohistochemistry. In the livers of rats treated with LQ, the protein and mRNA levels of multidrug resistance protein 2 and bile salt export pump were increased in the liver, which was verified by their increased localizations in canalicular membrane. In addition, LQ treatment enhanced the expression levels of major hepatic phase-II enzymes. Consistent with these results, LQ treatments attenuated galactosamine/LPS-induced hepatitis in rats, as supported by decreases in the plasma alanine aminotransferase, liver necrosis, and plasma TNF-α. These results demonstrate that LQ has a choleretic effect and the ability to induce transporters and phase-II enzymes in the liver, which may be associated with a hepatoprotective effect against galactosamine/LPS. Our findings may provide insight into understanding the action of LQ and its therapeutic use for liver disease.
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Bazydlo-Guzenda, Katarzyna, Pawel Buda, Mateusz Mach, Jerzy Pieczykolan, Izabela Kozlowska, Michal Janiszewski, Ewa Drzazga et al. "Evaluation of the hepatotoxicity of the novel GPR40 (FFAR1) agonist CPL207280 in the rat and monkey". PLOS ONE 16, n.º 9 (23 de septiembre de 2021): e0257477. http://dx.doi.org/10.1371/journal.pone.0257477.
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GPR40 (FFAR1) is a promising target for the managing type 2 diabetes (T2D). The most advanced GPR40 agonist TAK-875 exhibited satisfactory glucose-lowering effects in phase II and III studies. However, the phase III studies of TAK-875 revealed drug-induced liver injury (DILI). It is unknown whether DILI is a consequence of a specific GPR40 agonist or is an inherent feature of all GPR40 agonists. CPL207280 is a novel GPR40 agonist that improves diabetes in Zucker Diabetic Fatty (ZDF) rats, Goto Kakizaki (GK) rats and db/db mice. In this report, the DILI-related toxicity of CPL207280 was compared directly with that of TAK-875. In vitro studies evaluating hepatic biliary transporter inhibition, mitochondrial function, and metabolic profiling were performed in hepatocytes from different species. The long term toxicity of CPL207280 was studied in vivo in rats and monkeys. Activity of CPL207280 was one order of magnitude lesser than that of TAK-875 for the inhibition of bile acid transporters. CPL207280 had a negligible effect on the hepatic mitochondria. In contrast to TAK-875, which was metabolized through toxic glucuronidation, CPL207280 was metabolized mainly through oxidation. No deleterious hepatic effects were observed in chronically treated healthy and diabetic animals. The study presents promising data on the feasibility of creating a liver-safe GPR40 agonist. Additionally, it can be concluded that DILI is not a hallmark of GPR40 agonists; it is linked to the intrinsic properties of an individual agonist.
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Vollmar, Johanna, Yong Ook Kim, Jens U. Marquardt, Diana Becker, Peter R. Galle, Detlef Schuppan y Tim Zimmermann. "Deletion of organic cation transporter Oct3 promotes hepatic fibrosis via upregulation of TGFβ". American Journal of Physiology-Gastrointestinal and Liver Physiology 317, n.º 2 (1 de agosto de 2019): G195—G202. http://dx.doi.org/10.1152/ajpgi.00088.2019.
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Organic cation transporters (OCT) are responsible for the intracellular uptake and detoxification of a broad spectrum of endogenous and exogenous substrates. OCTs are downregulated in cholestasis, fibrosis, and hepatocellular carcinoma, but the underlying molecular mechanisms and downstream effects of OCT deletion are unknown. Oct3-knockout ( Oct3−/−; FVB.Slc22a3tm10pb) and wild-type (WT; FVB) mice were subject to escalating doses of carbon tetrachloride (CCl4) or thioacetamide (TAA) for 6 wk to induce advanced parenchymal liver fibrosis. Secondary biliary fibrosis was generated by bile duct ligation. Liver fibrosis was assessed by hydroxyproline determination, quantitative Sirius red morphometry, and quantitative real-time PCR for fibrosis and inflammation-related genes. Ductular reaction was assessed by bile duct count per field of view in hematoxylin and eosin staining. General gene expression analyses were performed in liver tissue from untreated Oct3−/− and WT mice. Finally, primary murine hepatocytes were treated with the nonselective OCT inhibitor quinine, and transforming growth factor-β1 ( Tgfβ1) protein expression was quantified by quantitative real-time PCR and Western blot. Oct3−/− mice developed significantly more fibrosis after bile duct ligation and CCl4 treatment compared with WT mice. Ductular reaction was enhanced in the long-term model. Concomitantly, Oct1 mRNA expression was downregulated during cholestatic and chemically (TAA and CCl4) induced fibrogenesis. The downregulation of Oct1 mRNA in fibrotic liver tissue reversed within 4 wk after TAA cessation. Gene expression analysis by next-generation sequencing revealed an enrichment of Tgfβ1 target genes in Oct3−/− mice. Tgfβ1 mRNA expression was significantly upregulated after chemically induced fibrosis ( P < 0.001) in Oct3−/− compared with WT mice. Accordingly, in primary murine hepatocytes functional inhibition of OCT led to an upregulation of Tgfβ1 mRNA expression. Loss of Oct3 promotes fibrogenesis by affecting Tgfβ-mediated homeostasis in mice with chronic biliary and parenchymal liver damage and fibrosis. NEW & NOTEWORTHY We show for the first time that organic cation transporter 3 (Oct3) is not only downregulated in fibrosis but loss of Oct3 also leads to an upregulation of transforming growth factor-β contributing to fibrosis progression.
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Cao, Jingsong, Bruno Stieger, Peter J. Meier y Mary Vore. "Expression of rat hepatic multidrug resistance-associated proteins and organic anion transporters in pregnancy". American Journal of Physiology-Gastrointestinal and Liver Physiology 283, n.º 3 (1 de septiembre de 2002): G757—G766. http://dx.doi.org/10.1152/ajpgi.00126.2002.
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The expression of hepatic multidrug resistance-associated protein (Mrp)1, 2, 3, and 6 and organic anion transporting polypeptides (Oatp)1 and 2 were examined in control and 20- to 21-day pregnant rats. Western analysis showed that expression of Oatp2 was decreased 50% in pregnancy, whereas expression of Oatp1 did not change. Expression of Mrp2 protein determined by Western analysis of total liver homogenate decreased to 50% of control levels in pregnant rats, consistent with studies using plasma membranes. Confocal immunohistochemistry showed that Mrp2 expression was confined to the canalicular membrane in both control and pregnant rats and was not detectable in intracellular compartments. In isolated perfused liver, the biliary excretion of 2,4-dintrophenyl-glutathione was significantly decreased in pregnancy, consistent with decreased expression of Mrp2. The expression of the basolateral transporter Mrp1 was not altered in pregnancy, whereas expression of Mrp6 mRNA was decreased by 60%. Expression of Mrp3 was also decreased by 50% in pregnant rat liver, indicating differential regulation of Mrp isoforms in pregnancy. These data also demonstrate that decreased Mrp2 expression is not necessarily accompanied by increased Mrp3 expression.
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Subali, Dionysius, Mi Hye Kwon, Won Seok Bang y Hee Eun Kang. "The pharmacokinetics of mycophenolic acid in rats with orotic acid induced nonalcoholic fatty liver disease". Canadian Journal of Physiology and Pharmacology 98, n.º 3 (marzo de 2020): 169–76. http://dx.doi.org/10.1139/cjpp-2019-0383.
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Post-transplantation nonalcoholic fatty liver disease (NAFLD) is common in liver transplant recipients. Changes in the expression levels and activities of drug-metabolizing enzymes and drug transporters have been reported in patients with NAFLD and relevant rodent models. Here, we evaluated whether the pharmacokinetics of mycophenolic acid (MPA), an immunosuppressant, would be altered in rats with NAFLD. NAFLD was induced by feeding a diet containing 1% (w/w) orotic acid for 20 days. The extent of hepatic glucuronidation of MPA to a major metabolite, mycophenolic acid-7-O-glucuronide (MPAG), did not differ between rats with NAFLD and controls. The expression levels of hepatic multidrug resistance-associated protein 2, responsible for biliary excretion of MPAG, were comparable in rats with NAFLD and controls; the biliary excretion of MPAG was also similar in the two groups. Compared with control rats, rats with NAFLD did not exhibit significant changes in the areas under the plasma concentration – time curves of MPA or MPAG after intravenous (5 mg/kg) or oral (10 mg/kg) administration of MPA. However, delayed oral absorption of MPA was observed in rats with NAFLD compared with controls; the MPA and MPAG peak plasma concentrations fell significantly and the times to achieve them were prolonged following oral administration of MPA.
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Farasyn, Taleah, Chao Xu y Wei Yue. "Development of a Rat Sandwich-Cultured Hepatocytes Model Expressing Functional Human Organic Anion Transporting Polypeptide (OATP) 1B3: A Potential Screening Tool for Liver-Targeting Compounds". Journal of Pharmacy & Pharmaceutical Sciences 24 (11 de septiembre de 2021): 475–83. http://dx.doi.org/10.18433/jpps31818.
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Purpose: Organic anion transporting polypeptide (OATP) 1B3 transports many clinically important drugs, including statins, from blood into the liver. It exclusively expresses in human liver under normal physiological conditions. There is no rodent ortholog of human OATP1B3. Tissue targeting of therapeutic molecules mediated by transporters, including liver-targeting via liver-specific OATPs, is an emerging area in drug development. Sandwich-cultured primary hepatocytes (SCH) are a well characterized in vitro model for assessment of hepatic drug uptake and biliary excretion. The current study was designed to develop a novel rat SCH model expressing human OATP1B3 to study the hepatic disposition of OATP1B3 substrates. Methods: Primary rat hepatocytes transduced with adenoviral vectors expressing FLAG-tagged OATP1B3 (Ad-OATP1B3), a control vector Ad-LacZ, or that were non-transduced were cultured in a sandwich configuration. FLAG immunoblot and immunofluorescence-staining determined expression and localization of OATP1B3. Uptake of [3H]-cholecystokinin octapeptide (CCK-8), a specific OATP1B3 substrate, was determined. Taurocholate (TC) is a substrate routinely used in SCH to assess biliary excretion via bile canaliculi (BC) and is also a substrate of OATP1B3. [3H]-TC accumulation in cells+BC, cells, biliary excretion index (BEI) and in vitro Clbiliary were determined using B-CLEAR® technology. Results: OATP1B3 protein was extensively expressed and primarily localized on the plasma membrane in day 4 Ad-OATP1B3-transduced rat SCH. [3H]-CCK-8 accumulation in cells+BC was significantly greater (~5-13 folds, p<0.001) in day 4 SCH with vs. without Ad-OATP1B3-transduction. Expressing OATP1B3 in rat SCH significantly increased [3H]-TC accumulation in cells+BC and cells, without affecting BEI and in vitro Clbiliary. Conclusions: Rat SCH expressing human OATP1B3-is a novel in vitro model allowing simultaneous assessment of hepatic uptake, hepatocellular accumulation and biliary excretion process of a human OATP1B3 substrate. This model could be a potential tool for screening for liver-targeting compounds mediated by OATP1B3.
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Thorling, Camilla A., Michael S. Roberts, Xin Liu, Linda M. Fletcher, Darrell Crawford y Frank J. Burczynski. "Effects of Long-Term Hepatic Ischemia-Reperfusion Injury on the Function of P-glycoprotein in vivo in Rats". Journal of Pharmacy & Pharmaceutical Sciences 17, n.º 1 (20 de marzo de 2014): 121. http://dx.doi.org/10.18433/j33c7b.
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PURPOSE: Ischemia-reperfusion injury is a common complication in liver surgery with oxidative stress related graft failure as a potential complication. The oxidative stress could affect hepatic drug transporters such as P-glycoprotein, which is crucial in the hepatic clearance of certain immunosuppressant drugs. Thus,, it is important to study its function after ischemia-reperfusion injury in vivo. Rhodamine 123 is a fluorescent substrate of P-glycoprotein and its hepatic disposition can be visualized using multiphoton microscopy in vivo using anaesthetized animals. The aim of this study was to investigate the effect of long-term ischemia-reperfusion injury on P-glycoprotein function in hepatocytes using in vivo multiphoton microscopy. METHODS: Localized ischemia was induced for 1 hour in rats. The liver was reperfused for 4, 24, 48 hours or 1 week, where-after rhodamine 123 was injected intravenously. Multiphoton microscopy imaged the liver and bile was collected continuously up to 6 hours following drug administration. The liver was harvested for histology andprotein expression of P-glycoprotein. RESULTS: Ischemia-reperfusion injury resulted in extensive liver damage, inflammatory cell infiltration and apoptosis in the midzonal and centrilobular regions of the liver acinus. P-glycoprotein protein expression decreased. Cellular concentration of rhodamine 123 increased as visualized by multiphoton microscopy, which was confirmed with decreased excretion of rhodamine 123 in collected bile. CONCLUSIONS: This study showed reduced function of P-glycoprotein in ischemia-reperfusion injury as reflected by decreased biliary excretion of Rhodamine 123, as well as reduced protein expression of the transporter. Multiphoton microscopy could be used to visualize and quantitate the intracellular levels of rhodamine 123. These findings stipulate the importance of using multiphoton microscopy to understand transmembrane drug flux and reflect on careful drug dosing after hepatic surgery. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
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Singla, Amika, Qing Chen, Kohei Suzuki, Jie Song, Alina Fedoseienko, Melinde Wijers, Adam Lopez, Daniel D. Billadeau, Bart van de Sluis y Ezra Burstein. "Regulation of murine copper homeostasis by members of the COMMD protein family". Disease Models & Mechanisms 14, n.º 1 (1 de diciembre de 2020): dmm045963. http://dx.doi.org/10.1242/dmm.045963.
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ABSTRACTCopper is an essential transition metal for all eukaryotes. In mammals, intestinal copper absorption is mediated by the ATP7A copper transporter, whereas copper excretion occurs predominantly through the biliary route and is mediated by the paralog ATP7B. Both transporters have been shown to be recycled actively between the endosomal network and the plasma membrane by a molecular machinery known as the COMMD/CCDC22/CCDC93 or CCC complex. In fact, mutations in COMMD1 can lead to impaired biliary copper excretion and liver pathology in dogs and in mice with liver-specific Commd1 deficiency, recapitulating aspects of this phenotype. Nonetheless, the role of the CCC complex in intestinal copper absorption in vivo has not been studied, and the potential redundancy of various COMMD family members has not been tested. In this study, we examined copper homeostasis in enterocyte-specific and hepatocyte-specific COMMD gene-deficient mice. We found that, in contrast to effects in cell lines in culture, COMMD protein deficiency induced minimal changes in ATP7A in enterocytes and did not lead to altered copper levels under low- or high-copper diets, suggesting that regulation of ATP7A in enterocytes is not of physiological consequence. By contrast, deficiency of any of three COMMD genes (Commd1, Commd6 or Commd9) resulted in hepatic copper accumulation under high-copper diets. We found that each of these deficiencies caused destabilization of the entire CCC complex and suggest that this might explain their shared phenotype. Overall, we conclude that the CCC complex plays an important role in ATP7B endosomal recycling and function.
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Kosters, Astrid, Raoul J. J. M. Frijters, Frank G. Schaap, Edwin Vink, Torsten Plösch, Roelof Ottenhoff, Milan Jirsa, Iris M. De Cuyper, Folkert Kuipers y Albert K. Groen. "Relation between hepatic expression of ATP-binding cassette transporters G5 and G8 and biliary cholesterol secretion in mice". Journal of Hepatology 38, n.º 6 (junio de 2003): 710–16. http://dx.doi.org/10.1016/s0168-8278(03)00093-x.
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Amador, Molly H. B. y M. Danielle McDonald. "The serotonin transporter and nonselective transporters are involved in peripheral serotonin uptake in the Gulf toadfish, Opsanus beta". American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 315, n.º 6 (1 de diciembre de 2018): R1154—R1166. http://dx.doi.org/10.1152/ajpregu.00137.2018.
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In mammals, circulating serotonin [5-hydroxytryptamine (5-HT)] is sequestered by platelets via the 5-HT transporter (SERT) to prevent unintended signaling by this potent signaling molecule. Teleost fish appear to lack a similar circulating storage pool, although the diverse effects of 5-HT in teleosts likely necessitate an alternative method of tight regulation, such as uptake by peripheral tissues. Here, a 5-HT radiotracer was used to explore the 5-HT uptake capacity of peripheral tissues in the Gulf toadfish, Opsanus beta, and to elucidate the primary excretion routes of 5-HT and its metabolites. Pharmacological inhibition of SERT and other transporters enabled assessment of the SERT dependence of peripheral 5-HT uptake and excretion. The results indicated a rapid and substantial uptake of 5-HT by the heart atrium, heart ventricle, and gill that was at least partly SERT dependent. The results also supported the presence of a partial blood-brain barrier that prevented rapid changes in brain 5-HT content despite fluctuating plasma 5-HT concentrations. The renal pathway appeared to be the dominant excretory route for 5-HT and its metabolites over shorter time frames (up to ~30 min), but hepatic excretion was substantial over several hours. SERT inhibition ultimately reduced the excretion of 5-HT and its metabolites by urinary, biliary, and/or intestinal pathways. In addition, branchial excretion of 5-HT and its metabolites could not be ruled out. In summary, this study reveals that the toadfish heart and gill play active roles in regulating circulating 5-HT and yields important insights into the control of peripheral 5-HT in this teleost fish.
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Meng, Qiang, Qi Liu, Changyuan Wang, Huijun Sun, Taiichi Kaku, Yukio Kato y Kexin Liu. "Molecular Mechanisms of Biliary Excretion of Cefditoren and the Effects of Cefditoren on the Expression Levels of Hepatic Transporters". Drug Metabolism and Pharmacokinetics 25, n.º 4 (2010): 320–27. http://dx.doi.org/10.2133/dmpk.dmpk-09-rg-092.
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Geuken, Erwin, Dorien S. Visser, Henri G. D. Leuvenink, Koert P. de Jong, Paul M. J. G. Peeters, Maarten J. H. Slooff, Folkert Kuipers y Robert J. Porte. "Hepatic expression of ABC transporters G5 and G8 does not correlate with biliary cholesterol secretion in liver transplant patients". Hepatology 42, n.º 5 (2005): 1166–74. http://dx.doi.org/10.1002/hep.20886.
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Chavez-Santoscoy, Rocio A., Janet A. Gutierrez-Uribe, Omar Granados, Ivan Torre-Villalvazo, Sergio O. Serna-Saldivar, Nimbe Torres, Berenice Palacios-González y Armando R. Tovar. "Flavonoids and saponins extracted from black bean (Phaseolus vulgaris L.) seed coats modulate lipid metabolism and biliary cholesterol secretion in C57BL/6 mice". British Journal of Nutrition 112, n.º 6 (24 de julio de 2014): 886–99. http://dx.doi.org/10.1017/s0007114514001536.
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Black bean (Phaseolus vulgaris L.) seed coats are a rich source of natural compounds with potential beneficial effects on human health. Beans exert hypolipidaemic activity; however, this effect has not been attributed to any particular component, and the underlying mechanisms of action and protein targets remain unknown. The aim of the present study was to identify and quantify primary saponins and flavonoids extracted from black bean seed coats, and to study their effects on lipid metabolism in primary rat hepatocytes and C57BL/6 mice. The methanol extract of black bean seed coats, characterised by a HPLC system with a UV–visible detector and an evaporative light-scattering detector and HPLC–time-of-flight/MS, contained quercetin 3-O-glucoside and soyasaponin Af as the primary flavonoid and saponin, respectively. The extract significantly reduced the expression of SREBP1c, FAS and HMGCR, and stimulated the expression of the reverse cholesterol transporters ABCG5/ABCG8 and CYP7A1 in the liver. In addition, there was an increase in the expression of hepatic PPAR-α. Consequently, there was a decrease in hepatic lipid depots and a significant increase in bile acid secretion. Furthermore, the ingestion of this extract modulated the proportion of lipids that was used as a substrate for energy generation. Thus, the results suggest that the extract of black bean seed coats may decrease hepatic lipogenesis and stimulate cholesterol excretion, in part, via bile acid synthesis.
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Perdomo, Virginia G., Juan P. Rigalli, Silvina S. M. Villanueva, María L. Ruiz, Marcelo G. Luquita, Claudia G. Echenique y Viviana A. Catania. "Modulation of Biotransformation Systems and ABC Transporters by Benznidazole in Rats". Antimicrobial Agents and Chemotherapy 57, n.º 10 (22 de julio de 2013): 4894–902. http://dx.doi.org/10.1128/aac.02531-12.
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ABSTRACTThe effect of antichagasic benznidazole (BZL; 100 mg/kg body weight/day, 3 consecutive days, intraperitoneally) on biotransformation systems and ABC transporters was evaluated in rats. Expression of cytochrome P-450 (CYP3A), UDP-glucuronosyltransferase (UGT1A), glutathioneS-transferases (alpha glutathioneS-transferase [GST-α], GST-μ, and GST-π), multidrug-resistance-associated protein 2 (Mrp2), and P glycoprotein (P-gp) in liver, small intestine, and kidney was estimated by Western blotting. Increases in hepatic CYP3A (30%) and GST-μ (40%) and in intestinal GST-α (72% in jejunum and 136% in ileum) were detected. Significant increases in Mrp2 (300%) and P-gp (500%) proteins in liver from BZL-treated rats were observed without changes in kidney. P-gp and Mrp2 were also increased by BZL in jejunum (170% and 120%, respectively). In ileum, only P-gp was increased by BZL (50%). The activities of GST, P-gp, and Mrp2 correlated well with the upregulation of proteins in liver and jejunum. Plasma decay of a test dose of BZL (5 mg/kg body weight) administered intraduodenally was faster (295%) and the area under the concentration-time curve (AUC) was lower (41%) for BZL-pretreated rats than for controls. The biliary excretion of BZL was higher (60%) in the BZL group, and urinary excretion of BZL did not show differences between groups. The amount of absorbed BZL in intestinal sacs was lower (25%) in pretreated rats than in controls. In conclusion, induction of biotransformation enzymes and/or transporters by BZL could increase the clearance and/or decrease the intestinal absorption of coadministered drugs that are substrates of these systems, including BZL itself.
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Huang, Yu, Yusuke Sakai, Takanobu Hara, Takeshi Katsuda, Takahiro Ochiya, Tomohiko Adachi, Masaaki Hidaka, Wei-Li Gu y Susumu Eguchi. "Development of Bifunctional Three-Dimensional Cysts from Chemically Induced Liver Progenitors". Stem Cells International 2019 (3 de septiembre de 2019): 1–13. http://dx.doi.org/10.1155/2019/3975689.
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Chemically induced liver progenitors (CLiPs) have promising applications in liver regenerative medicine. Three-dimensional (3D) structures generated from liver progenitor cells possess wide applications in cell transplantation, disease model, and drug testing. Here, we report on the spontaneous formation of 3D cystic structures comprising maturing rat CLiPs on gelatin-coated dishes. Our 3D cysts contained Alb+/+CK19+/− and Ck19+/+Alb+/− cells. These cell types gradually diverged into specialized mature cells, as demonstrated by the expression of mature biliary markers (Cftr, Ae2, and Aqp1) and hepatic markers (Alb and Mrp2). The 3D cysts also expressed functional multidrug resistance protein 1 (Mdr1), as indicated by epithelial efflux of rhodamine. Furthermore, we observed bile canaliculi functions between hepatocytes and cholyl-lysyl-fluorescein extrusions, indicating that the functional characteristics of 3D cysts and active bile salt export pump (Bsep) transporters were intact. Thus, our study revealed a natural characteristic of rat CLiPs to spontaneously form 3D cystic structures accompanied with cell maturation in vitro, offering a platform for studies of liver development and drug screening.
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Pradhan, Tirthadipa, Prithu Sundd, Mark T. Gladwin, Satdarshan Pal Monga y Gregory J. Kato. "Impaired Bile Secretion Promotes Chronic Liver Injury in Sickle Cell Disease". Blood 134, Supplement_1 (13 de noviembre de 2019): 3536. http://dx.doi.org/10.1182/blood-2019-131915.
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Hepatic crisis is an emergent complication affecting sickle cell disease (SCD) patients, however, the molecular mechanism of sickle cell hepatobiliary crisis remains poorly understood. We examined the liver pathophysiology of SCD using a humanized mouse model (townes SCD mice; homozygous for Hbatm1(HBA)Tow, homozygous for Hbbtm2(HBG1,HBB*)Tow). These mice have the major features (irreversibly sickled red cells, splenomegaly, anemia, multiorgan pathology) found in humans with SCD and, as such, represent a useful in vivo system to study hepatobiliary changes in SCD disease. SCD mice manifested progressive hepatomegaly, liver injury and hyperbilirubinemia. RNA-sequence analysis of total RNA from SCD mouse liver compared to control (AS) identified dysregulation of genes encoding proteins responsible for fibrosis, bile acid synthesis, bile transport and cholesterol metabolism. Immunohistochemical analysis confirmed inflammation, fibrosis and increased ductular reaction in SCD mice. To mechanistically address the cholestatic phenotype in SCD mice, we used our recently developed multi-photon-excitation (MPE) enabled in vivo real-time fluorescence microscopy of intact liver in live mice. We used Texas-Red (TXR) dextran to visualize the blood flow through liver sinusoids and carboxyfluorescein (used as a surrogate of bile flow) to visualize bile flow through biliary canaliculi. Real time imaging show that sinusoidal ischemia occurs in the liver of transgenic-humanized SCD mice under basal condition. Intravital imaging also revealed impaired bile secretion into the bile canaliculi, which was associated with loss of apical bile acid transporters and bile acid biosynthetic enzymes, hepatic bile accumulation, and activation of Farnesoid X receptor (FXR) and small heterodimer partner (Shp) in the liver of SCD mice. These findings are the first to identify that impaired bile acid synthesis and misexpression of bile transporters promote intrahepatic bile accumulation and impaired bile secretion, leading to hepatobiliary injury of SCD. Improved understanding of these processes could potentially benefit the development of new therapies to treat sickle cell hepatic crisis. Disclosures Gladwin: Globin Solutions, Inc: Patents & Royalties: Provisional patents for the use of recombinant neuroglobin and heme-based molecules as antidotes for CO poisoning; Bayer Pharmaceuticals: Other: Co-investigator; United Therapeutics: Patents & Royalties: Co-inventor on an NIH government patent for the use of nitrite salts in cardiovascular diseases . Kato:Novartis, Global Blood Therapeutics: Consultancy, Research Funding; Bayer: Research Funding.
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Martin, Gregory G., Barbara P. Atshaves, Avery L. Mcintosh, John T. Mackie, Ann B. Kier y Friedhelm Schroeder. "Liver fatty-acid-binding protein (L-FABP) gene ablation alters liver bile acid metabolism in male mice". Biochemical Journal 391, n.º 3 (25 de octubre de 2005): 549–60. http://dx.doi.org/10.1042/bj20050296.
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Although the physiological roles of the individual bile acid synthetic enzymes have been extensively examined, relatively little is known regarding the function of intracellular bile acid-binding proteins. Male L-FABP (liver fatty-acid-binding protein) gene-ablated mice were used to determine a role for L-FABP, the major liver bile acid-binding protein, in bile acid and biliary cholesterol metabolism. First, in control-fed mice L-FABP gene ablation alone increased the total bile acid pool size by 1.5-fold, especially in gall-bladder and liver, but without altering the proportions of bile acid, cholesterol and phospholipid. Loss of liver L-FABP was more than compensated by up-regulation of: other liver cytosolic bile acid-binding proteins [GST (glutathione S-transferase), 3α-HSD (3α-hydroxysteroid dehydrogenase)], key hepatic bile acid synthetic enzymes [CYP7A1 (cholesterol 7α-hydroxylase) and CYP27A1 (sterol 27α-hydroxylase)], membrane bile acid translocases [canalicular BSEP (bile salt export pump), canalicular MRP2 (multidrug resistance associated protein 2), and basolateral/serosal OATP-1 (organic anion transporting polypeptide 1)], and positive alterations in nuclear receptors [more LXRα (liver X receptor α) and less SHP (short heterodimer partner)]. Secondly, L-FABP gene ablation reversed the cholesterol-responsiveness of bile acid metabolic parameters such that total bile acid pool size, especially in gall-bladder and liver, was reduced 4-fold, while the mass of biliary cholesterol increased 1.9-fold. The dramatically reduced bile acid levels in cholesterol-fed male L-FABP (−/−) mice were associated with reduced expression of: (i) liver cytosolic bile acid-binding proteins (L-FABP, GST and 3α-HSD), (ii) hepatic bile acid synthetic enzymes [CYP7A1, CYP27A1 and SCP-x (sterol carrier protein-x/3-ketoacyl-CoA thiolase)] concomitant with decreased positive nuclear receptor alterations (i.e. less LXRα and more SHP), and (iii) membrane bile acid transporters (BSEP, MRP2 and OATP-1). These are the first results suggesting a physiological role for the major cytosolic bile acid-binding protein (L-FABP) in influencing liver bile metabolic phenotype and gall-bladder bile lipids of male mice, especially in response to dietary cholesterol.
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Guo, Cen, Kim L. R. Brouwer, Kenneth R. Brouwer, Paul W. Stewart y Caroline Mosley. "Probe Cocktail to Assess Transporter Function in Sandwich-Cultured Human Hepatocytes". Journal of Pharmacy & Pharmaceutical Sciences 22 (19 de noviembre de 2019): 567–75. http://dx.doi.org/10.18433/jpps30706.
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PURPOSE: Probe substrates are used routinely to assess transporter function in vitro. Administration of multiple probe substrates together as a “cocktail” in sandwich-cultured human hepatocytes (SCHH) could increase the throughput of transporter function assessment in a physiologically-relevant in vitro system. This study was designed to compare transporter function between cocktail and single agent administration in SCHH. METHODS: Rosuvastatin, digoxin, and metformin were selected as probe substrates of hepatic transporters OATP1B1, OATP1B3, BCRP, P-gp, and OCT1. Total accumulation (Cells+Bile) and biliary excretion index (BEI) values derived from administration of the cocktail were compared to values obtained after administration of single agents in the absence and presence of a model inhibitor, erythromycin estolate. RESULTS: For rosuvastatin and metformin accumulation, the ratio of means [90% confidence interval (CI)] for cocktail to single agent administration was 100% [94%, 106%] and 90% [82%, 99%], respectively. Therefore, the cocktail and single-agent mode of administration were deemed equivalent per standard equivalence criterion of 80-120% for rosuvastatin and metformin accumulation, but not for digoxin accumulation (77% [62%, 92%]). The ratio of means [90% CI] for rosuvastatin BEI values between the two administration modes (105% [97%, 114%]) also was deemed equivalent. The ratio for digoxin BEI values between the two administration modes was 99% [78%, 120%]. In the presence of erythromycin estolate, the two administration modes were deemed equivalent for evaluation of rosuvastatin, digoxin, and metformin accumulation; the ratio of means [90% CI] was 104% [94%, 115%], 94% [82%, 105%], and 100% [88%, 111%], respectively. However, rosuvastatin and digoxin BEI values were low and quite variable in the presence of the inhibitor, so the BEI results were inconclusive. CONCLUSIONS: These data suggest that rosuvastatin and metformin can be administered as a cocktail to evaluate the function of OATP1B1, OATP1B3, BCRP, and OCT1 in SCHH, and that digoxin may not be an ideal component of such a cocktail.
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Yamashiro, Wakaba, Kazuya Maeda, Masakazu Hirouchi, Yasuhisa Adachi, Zhuohan Hu y Yuichi Sugiyama. "INVOLVEMENT OF TRANSPORTERS IN THE HEPATIC UPTAKE AND BILIARY EXCRETION OF VALSARTAN, A SELECTIVE ANTAGONIST OF THE ANGIOTENSIN II AT1-RECEPTOR, IN HUMANS". Drug Metabolism and Disposition 34, n.º 7 (19 de abril de 2006): 1247–54. http://dx.doi.org/10.1124/dmd.105.008938.
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Wakabayashi, Yoshiyuki, Jennifer Lippincott-Schwartz y Irwin M. Arias. "Intracellular Trafficking of Bile Salt Export Pump (ABCB11) in Polarized Hepatic Cells: Constitutive Cycling between the Canalicular Membrane and rab11-positive Endosomes". Molecular Biology of the Cell 15, n.º 7 (julio de 2004): 3485–96. http://dx.doi.org/10.1091/mbc.e03-10-0737.
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The bile salt export pump (BSEP, ABCB11) couples ATP hydrolysis with transport of bile acids into the bile canaliculus of hepatocytes. Its localization in the apical canalicular membrane is physiologically regulated by the demand to secrete biliary components. To gain insight into how such localization is regulated, we studied the intracellular trafficking of BSEP tagged with yellow fluorescent protein (YFP) in polarized WIF-B9 cells. Confocal imaging revealed that BSEP-YFP was localized at the canalicular membrane and in tubulo-vesicular structures either adjacent to the microtubule-organizing center or widely distributed in the cytoplasm. In the latter two locations, BSEP-YFP colocalized with rab11, an endosomal marker. Selective photobleaching experiments revealed that single BSEP-YFP molecules resided in canalicular membranes only transiently before exchanging with intracellular BSEP-YFP pools. Such exchange was inhibited by microtubule and actin inhibitors and was unaffected by brefeldin A, dibutyryl cyclic AMP, taurocholate, or PI 3-kinase inhibitors. Intracellular carriers enriched in BSEP-YFP elongated and dissociated as tubular elements from a globular structure adjacent to the microtubule-organizing center. They displayed oscillatory movement toward either canalicular or basolateral membranes, but only fused with the canalicular membrane. The pathway between canalicular and intracellular membranes that BSEP constitutively cycles within could serve to regulate apical pools of BSEP as well as other apical membrane transporters.
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Sudhop, T. "Comparison of the hepatic clearances of campesterol, sitosterol, and cholesterol in healthy subjects suggests that efflux transporters controlling intestinal sterol absorption also regulate biliary secretion". Gut 51, n.º 6 (1 de diciembre de 2002): 860–63. http://dx.doi.org/10.1136/gut.51.6.860.
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Wang, David Q. H., Susumu Tazuma, David E. Cohen y Martin C. Carey. "Feeding natural hydrophilic bile acids inhibits intestinal cholesterol absorption: studies in the gallstone-susceptible mouse". American Journal of Physiology-Gastrointestinal and Liver Physiology 285, n.º 3 (septiembre de 2003): G494—G502. http://dx.doi.org/10.1152/ajpgi.00156.2003.
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We explored the influence of the hydrophilic-hydrophobic balance of a series of natural bile acids on cholesterol absorption in the mouse. Male C57L/J mice were fed standard chow or chow supplemented with 0.5% cholic; chenodeoxycholic; deoxycholic; dehydrocholic; hyocholic; hyodeoxycholic; α-, β-, or ω-muricholic; ursocholic; or ursodeoxycholic acids for 7 days. Biliary bile salts were measured by reverse-phase HPLC, and hydrophobicity indices were estimated by Heuman's method. Cholesterol absorption efficiency was determined by a plasma dual-isotope ratio method. In mice fed chow, natural proportions of tauro-β-muricholate (42 ± 6%) and taurocholate (50 ± 7%) with a hydrophobicity index of -0.35 ± 0.04 produced cholesterol absorption of 37 ± 5%. Because bacterial and especially hepatic biotransformations of specific bile acids occurred, hydrophobicity indices of the resultant bile salt pools differed from fed bile acids. We observed a significant positive correlation between hydrophobicity indices of the bile salt pool and percent cholesterol absorption. The principal mechanism whereby hydrophilic bile acids inhibit cholesterol absorption appears to be diminution of intraluminal micellar cholesterol solubilization. Gene expression of intestinal sterol efflux transporters Abcg5 and Abcg8 was upregulated by feeding cholic acid but not by hydrophilic β-muricholic acid nor by hydrophobic deoxycholic acid. We conclude that the hydrophobicity of the bile salt pool predicts the effects of individual fed bile acids on intestinal cholesterol absorption. Natural α- and β-muricholic acids are the most powerful inhibitors of cholesterol absorption in mice and might act as potent cholesterol-lowering agents for prevention of cholesterol deposition diseases in humans.
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Shin, H. C., Y. Kato, T. Yamada, K. Niinuma, A. Hisaka y Y. Sugiyama. "Hepatobiliary transport mechanism for the cyclopentapeptide endothelin antagonist BQ-123". American Journal of Physiology-Gastrointestinal and Liver Physiology 272, n.º 5 (1 de mayo de 1997): G979—G986. http://dx.doi.org/10.1152/ajpgi.1997.272.5.g979.
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The hepatobiliary transport of an anionic cyclopentapeptide endothelin antagonist, BQ-123, was studied in rats. Biliary excretion of [3H]BQ-123 was extensive in vivo (approximately 75% of intravenous infusion rates). Liver-to-plasma and bile-to-liver concentration ratios at steady state were approximately 3 and 200, respectively, suggesting that hepatic uptake and biliary excretion are concentrative processes. The biliary excretion clearance exhibited a saturation at a hepatic concentration of > 100 nmol/g liver and was markedly reduced in Eisai hyperbilirubinemic rats, which have a hereditary defect of canalicular multispecific organic anion transporter. An ATP-dependent and saturable uptake of BQ-123 by isolated canalicular membrane vesicles was observed in vitro. Impaired transport of BQ-123 was also confirmed in canalicular membrane vesicles prepared from Eisai hyperbilirubinemic rats. These results demonstrate that the biliary excretion process is ATP-driven primary active transport. It is proposed that a canalicular multispecific organic anion transporter is mainly responsible for the biliary excretion of BQ-123.
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Tancevski, Ivan, Andreas Wehinger, Egon Demetz, Philipp Eller, Kristina Duwensee, Julia Huber, Kathrin Hochegger et al. "Reduced Plasma High-Density Lipoprotein Cholesterol in Hyperthyroid Mice Coincides with Decreased Hepatic Adenosine 5′-Triphosphate-Binding Cassette Transporter 1 Expression". Endocrinology 149, n.º 7 (3 de abril de 2008): 3708–12. http://dx.doi.org/10.1210/en.2007-1387.
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The aim of the study was to investigate the influence of severe hyperthyroidism on plasma high-density lipoprotein cholesterol (HDL-C). Recently, it was shown in mice that increasing doses of T3 up-regulate hepatic expression of scavenger receptor class B, type I, resulting in increased clearance of plasma HDL-C. Here, we show that severe hyperthyroidism in mice did not affect hepatic expression of scavenger receptor class B, type I, but reduced hepatic expression of ATP-binding cassette transporter 1, accompanied by a 40% reduction of HDL-C. The sterol content of bile, liver, and feces was markedly increased, accompanied by up-regulation of hepatic cholesterol 7α-hydroxylase, and ATP-binding cassette transporter 5, which is known to promote biliary sterol secretion upon dimerization with ATP-binding cassette transporter 8. Both control and hyperthyroid mice exerted identical plasma clearance of iv injected [3H]HDL-C, supporting the view that severe hyperthyroidism does not affect HDL-C clearance but, rather, its formation via hepatic ATP-binding cassette transporter 1.
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Perry, Cassandra H., William R. Smith, Robert L. St. Claire y Kenneth R. Brouwer. "Automated Applications of Sandwich-Cultured Hepatocytes in the Evaluation of Hepatic Drug Transport". Journal of Biomolecular Screening 16, n.º 4 (10 de marzo de 2011): 427–35. http://dx.doi.org/10.1177/1087057111400192.
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Predictions of the absorption, distribution, metabolism, excretion, and toxicity of compounds in pharmaceutical development are essential aspects of the drug discovery process. B-CLEAR is an in vitro system that uses sandwich-cultured hepatocytes to evaluate and predict in vivo hepatobiliary disposition (hepatic uptake, biliary excretion, and biliary clearance), transporter-based hepatic drug-drug interactions, and potential drug-induced hepatotoxicity. Automation of predictive technologies is an advantageous and preferred format in drug discovery. In this study, manual and automated studies are investigated and equivalence is demonstrated. In addition, automated applications using model probe substrates and inhibitors to assess the cholestatic potential of drugs and evaluate hepatic drug transport are examined. The successful automation of this technology provides a more reproducible and less labor-intensive approach, reducing potential operator error in complex studies and facilitating technology transfer.
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Marie, Solène, Irene Hernández-Lozano, Louise Breuil, Wadad Saba, Anthony Novell, Jean-Luc Gennisson, Oliver Langer, Charles Truillet y Nicolas Tournier. "Validation of Pharmacological Protocols for Targeted Inhibition of Canalicular MRP2 Activity in Hepatocytes Using [99mTc]mebrofenin Imaging in Rats". Pharmaceutics 12, n.º 6 (27 de mayo de 2020): 486. http://dx.doi.org/10.3390/pharmaceutics12060486.
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The multidrug resistance-associated protein 2 (MRP2) mediates the biliary excretion of drugs and metabolites. [99mTc]mebrofenin may be employed as a probe for hepatic MRP2 activity because its biliary excretion is predominantly mediated by this transporter. As the liver uptake of [99mTc]mebrofenin depends on organic anion-transporting polypeptide (OATP) activity, a safe protocol for targeted inhibition of hepatic MRP2 is needed to study the intrinsic role of each transporter system. Diltiazem (DTZ) and cyclosporin A (CsA) were first confirmed to be potent MRP2 inhibitors in vitro. Dynamic acquisitions were performed in rats (n = 5–6 per group) to assess the kinetics of [99mTc]mebrofenin in the liver, intestine and heart-blood pool after increasing doses of inhibitors. Their impact on hepatic blood flow was assessed using Doppler ultrasound (n = 4). DTZ (s.c., 10 mg/kg) and low-dose CsA (i.v., 0.01 mg/kg) selectively decreased the transfer of [99mTc]mebrofenin from the liver to the bile (k3). Higher doses of DTZ and CsA did not further decrease k3 but dose-dependently decreased the uptake (k1) and backflux (k2) rate constants between blood and liver. High dose of DTZ (i.v., 3 mg/kg) but not CsA (i.v., 5 mg/kg) significantly decreased the blood flow in the portal vein and hepatic artery. Targeted pharmacological inhibition of hepatic MRP2 activity can be achieved in vivo without impacting OATP activity and liver blood flow. Clinical studies are warranted to validate [99mTc]mebrofenin in combination with low-dose CsA as a novel substrate/inhibitor pair to untangle the role of OATP and MRP2 activity in liver diseases.