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1
Hannan, Md Abdul, Md Sarwar Zahan, Partha Protim Sarker, Akhi Moni, Hunjoo Ha, and Md Jamal Uddin. "Protective Effects of Black Cumin (Nigella sativa) and Its Bioactive Constituent, Thymoquinone against Kidney Injury: An Aspect on Pharmacological Insights." International Journal of Molecular Sciences 22, no. 16 (August 23, 2021): 9078. http://dx.doi.org/10.3390/ijms22169078.
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The prevalence of chronic kidney disease (CKD) is increasing worldwide, and a close association between acute kidney injury (AKI) and CKD has recently been identified. Black cumin (Nigella sativa) has been shown to be effective in treating various kidney diseases. Accumulating evidence shows that black cumin and its vital compound, thymoquinone (TQ), can protect against kidney injury caused by various xenobiotics, namely chemotherapeutic agents, heavy metals, pesticides, and other environmental chemicals. Black cumin can also protect the kidneys from ischemic shock. The mechanisms underlying the kidney protective potential of black cumin and TQ include antioxidation, anti-inflammation, anti-apoptosis, and antifibrosis which are manifested in their regulatory role in the antioxidant defense system, NF-κB signaling, caspase pathways, and TGF-β signaling. In clinical trials, black seed oil was shown to normalize blood and urine parameters and improve disease outcomes in advanced CKD patients. While black cumin and its products have shown promising kidney protective effects, information on nanoparticle-guided targeted delivery into kidney is still lacking. Moreover, the clinical evidence on this natural product is not sufficient to recommend it to CKD patients. This review provides insightful information on the pharmacological benefits of black cumin and TQ against kidney damage.
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Меликова, E. Melikova, Брин, and Vadim Brin. "The Effects of Ammonium Molybdate on Renal Function in the Rats after Parathyreoidectomy." Journal of New Medical Technologies 20, no. 4 (December 20, 2013): 71–73. http://dx.doi.org/10.12737/2733.
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The constant pollution of the environment increases the content of xenobiotics in the air, soil, water and contributes to their entry into the organism. Increased content of molybdenum in the environment has pathogenic effect on the human organism. It is known that the excretion of metals is mainly via the kidney, while the content of the xenobiotics in the urine may have pathogenic effects on renal function. It is of interest to study the renal functions in conditions of inflow metals in the organism.
The aim of this work was to study the effect of experimental hypocalcaemia on uropoisis renal function at the chronic molybdenum intoxication.
Materials and methods. Experiments were carried out on Wistar-rats. Chronic molybdenum intoxication in experimental animals was caused by intragastric injection of ammonium molybdate solution in the dose of 50mg/kg. during 1 month. Experimental hypocalcaemia was created by the parathyroidectomy.
Results. It was noted that when a stand-alone injection of ammonium molybdate glomerular filtration rate is reduced. In the model combined with parathyroidectomy this indicator comes back to normal. Tubular water reabsorption, urinary excretion of calcium and
protein are less pronounced than in the isolated introduction ammonium molybdate. Urine osmolarity also had a tendency to decrease. Conclusions. Experimental hypocalcaemia reduces the renal manifestations of chronic molybdenum intoxication.
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Moniruzzaman, M., MM Khan, MK Rahman, and MS Islam. "Effects of profenofos induced histopathology and recovery patterns in silver barb (Barbonymus gonionotus)." Progressive Agriculture 28, no. 3 (November 24, 2017): 240–48. http://dx.doi.org/10.3329/pa.v28i3.34661.
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Histopathology is promising field for research in aquatic toxicology as it provides the real picture of the toxic effects of xenobiotics in vital functions of a living organism. The present study aims to evaluate the toxic effect of pesticide namely profenofos on silver barb. Liver and kidney of silver barb were examined histologically after exposure to sublethal concentrations (0.01 ppm, 10% of LC50 and 0.05 ppm, 50% of LC50) of profenofos for 0, 7, 15 and 30 days. Histological recovery was also studied by maintaining the pesticide‐exposed fish in a freshwater system for an additional 7, 15 and 30 day. Kidney and liver of exposed individuals exhibited some remarkable changes in their histology in comparison to control and recovery group. Hepatic lesions in the liver tissues of fish were characterized by cloudy swelling of hepatocytes, lipoid vacuoles, pycnotic nuclei and focal necrosis. Epithelial hypertrophy, narrowing of the tubular lumen, atrophy of the glomerulus, broader Bowman's capsule, necrosis in the epithelial cells and pycnosis in the hematopoietic tissue were observed in kidney tissues of experimental fish. These lesions grew with increasing concentration. Although some of the changes were reversible, the rest were less pronounced after a recovery period.Progressive Agriculture 28 (3): 240-248, 2017
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Veiga-Matos, Jéssica, Fernando Remião, and Ana Motales. "Pharmacokinetics and Toxicokinetics Roles of Membrane Transporters at Kidney Level." Journal of Pharmacy & Pharmaceutical Sciences 23 (September 29, 2020): 333–56. http://dx.doi.org/10.18433/jpps30865.
Full textAbstract:
Transporters are large membrane proteins, which control the passage of various compounds through biological membranes. These proteins are divided into uptake and efflux transporters and play an important role in the toxicokinetics of many endobiotics and xenobiotics. The uptake transporters facilitate the absorption of these compounds from the blood into the proximal tubular cells, while the efflux transporters eliminate these compounds into tubular fluid (urine). Overall, the uptake is performed by the superfamily solute carrier (SLC) transporters, which are, mostly, located in the basolateral membrane. The organic anion transporters (OATs; SLC22), the organic cation transporters (OCTs; SLC22), the organic cation/carnitine transporters (OCTNs), and the organic anion transporting polypeptides (OATP; SLC21/SLCO) are some examples of uptake transporters of the SLC superfamily. On the other hand, the superfamily ATP-binding cassette (ABC) transporters carry out the elimination of the substances through the apical membrane of the proximal tubular cells. The multidrug resistance proteins 1 (MDR; ABCB), the multi resistance protein (MRP2; ABCC) and the breast cancer resistance protein (BCRP, ABCG) along with the multidrug and toxin extrusion (MATE), which is an SLC transporter, carry out the substance efflux of the cell, However, uptake transporters seem to be more efficient than efflux transporters, leading to an accumulation of compounds in proximal tubular cells and, consequently, to renal damage. The accumulation of compounds can also occur due to variations in the number of transporters that exist due to differences in sex, age, genetic polymorphisms and epigenetics. Furthermore, some substances can inhibit, induce or, eventually, activate these transporters, with consequent drug-drug interactions (DDIs) as a result of alterations on the toxicokinetics of xenobiotics, leading to an increase of their accumulation and, consequently, to renal damage. These compounds may be exogenous, such as antibiotics, antivirals, cisplatin, metals, herbicides, mycotoxins and drugs; or endogenous, like uric acid, bile acids, bilirubin conjugates and conjugated steroids. Thus, in this review, we will focus on the accumulation of exogenous compounds due to variations on renal transporters and the consequent biological effects caused by them.
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Benourad, Fouzia, Zehra-Cagla Kahvecioglu, Mokhtar Youcef-Benkada, and Jean-Marie Colet. "Protective potential of the essential oil of Thymus vulgaris L. against Dicofol-induced poisoning in rats as established through clinical chemistry, histopathology and 1H-NMR-based metabonomics." South Asian Journal of Experimental Biology 8, no. 2 (January 14, 2019): 49–56. http://dx.doi.org/10.38150/sajeb.8(2).p49-56.
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Pesticides, organochlorines, analogues and derivatives of DDT, those are all terms often associated with health risks, intoxications, nephropathies and other hepatotoxicities. These are phytosanitary products that interfere with the internal metabolism of sensitive organs, such as the kidney or the liver, which orchestrate the metabolism and elimina on of xenobiotics. In this study, a group of Wistar rats was intraperitoneally exposed to Dicofol, a pesticide analogue of DDT. A second group received preven ve injec ons of a diluted thyme essen al oil solu on for four days before exposure to Dicofol. The evaluation of the toxic effects possibly induced by Dicofol in the two experimental groups was carried out using a mul disciplinary approach in- cluding clinical chemistry, histopathology and 1H-NMR-based metabonomics. Histopathological examina on showed pulmonary in amma on and kidney damage in the group exposed to Dicofol. The metabonomic study revealed metabolic disturbances in the liver and kidney. The protective role of the essential oil of thyme was clearly demonstrated from the metabonomic profiles and was confirmed by histological examina on of organs.
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Ilina, E. N., E. M. Mayorova, A. I. Manolov, A. A. Korenkova, V. V. Bahmetjev, and K. S. Gorbunov. "Gut Microbiome and Drug Metabolism." Biomedical Chemistry: Research and Methods 4, no. 1 (January 2021): e00146. http://dx.doi.org/10.18097/bmcrm00146.
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The human physiology textbooks traditionally consider the intestine as a metabolically active organ, with its activity primarily associated with the production of numerous digestive enzymes. The development of molecular analysis technologies has significantly detailized this picture, primarily by decoding the metabolic potential of the intestinal microbiota. Data from numerous metagenomic studies indicate that the number of eukaryotic and bacterial cells in the human body is comparable - about 3.0×1013, while the number of genes in the intestinal metagenome is one hundred times greater than in the human genome. Obviously, the gut microbiota exhibits both direct and indirect effects on the metabolism of drugs and xenobiotics, that can affect their effectiveness and toxicity. Orally administrated xenobiotics have been found to be metabolized by intestinal microbial enzymes before being absorbed from the gastrointestinal tract into the blood flow. The metabolic reactions performed by the gut microbiota greatly differ from the metabolic reactions of the liver, providing modification of drugs by acetylation, deacetylation, decarboxylation, dehydroxylation, demethylation, dehalogenation, etc. Despite the metabolism of xenobiotics by microbial enzymes of the intestine is rather known, information about the specific microflora mediating each metabolic reaction is still limited, mainly by the lack of an adequate model of the intestinal microbial community to allow the accumulation of experimental data for the creation of computational models. Currently, studies of drug metabolism use microfluidic chips, reproducing functions of various organs and tissues, such as the liver, kidney, lungs and intestine, as in vitro models in the form of 2D and 3D cell cultures. Supplementation of such systems with the microbial community will allow to get as close as possible to in vitro modeling of complicated biological processes in the interests of pharmacological research and the accumulation of data for constructing computational models.
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Politis, Maria D., Jacob C. Freedman, Erin N. Haynes, and Alison P. Sanders. "Association of Manganese Biomarker Concentrations with Blood Pressure and Kidney Parameters among Healthy Adolescents: NHANES 2013–2018." Children 8, no. 10 (September 25, 2021): 846. http://dx.doi.org/10.3390/children8100846.
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Deficiency or excess exposure to manganese (Mn), an essential mineral, may have potentially adverse health effects. The kidneys are a major organ of Mn site-specific toxicity because of their unique role in filtration, metabolism, and excretion of xenobiotics. We hypothesized that Mn concentrations were associated with poorer blood pressure (BP) and kidney parameters such as estimated glomerular filtration rate (eGFR), blood urea nitrogen (BUN), and albumin creatinine ratio (ACR). We conducted a cross-sectional analysis of 1931 healthy U.S. adolescents aged 12–19 years participating in National Health and Nutrition Examination Survey cycles 2013–2014, 2015–2016, and 2017–2018. Blood and urine Mn concentrations were measured using inductively coupled plasma mass spectrometry. Systolic and diastolic BP were calculated as the average of available readings. eGFR was calculated from serum creatinine using the Bedside Schwartz equation. We performed multiple linear regression, adjusting for age, sex, body mass index, race/ethnicity, and poverty income ratio. We observed null relationships between blood Mn concentrations with eGFR, ACR, BUN, and BP. In a subset of 691 participants, we observed that a 10-fold increase in urine Mn was associated with a 16.4 mL/min higher eGFR (95% Confidence Interval: 11.1, 21.7). These exploratory findings should be interpreted cautiously and warrant investigation in longitudinal studies.
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AIGNER, Achim, Martina JÄGER, Ralf PASTERNACK, Peter WEBER, Dirk WIENKE, and Sabine WOLF. "Purification and characterization of cysteine-S-conjugate N-acetyltransferase from pig kidney." Biochemical Journal 317, no. 1 (July 1, 1996): 213–18. http://dx.doi.org/10.1042/bj3170213.
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Microsomal cysteine-S-conjugate N-acetyltransferase catalyses the N-acetylation of various S-substituted cysteines in liver and kidney. We describe here the purification and more detailed characterization of this enzyme catalysing the final reaction of mercapturic acid biosynthesis, and thus playing a crucial role in the detoxicating metabolism of many xenobiotics. The solubilization of cysteine-S-conjugate N-acetyltransferase by deoxy-BIGCHAP [N,N´-bis-(3-d-gluconamidopropyl)deoxycholamide] was the prerequisite for partial purification by means of anion-exchange chromatography. The molecular mass of the enzyme was determined by gel filtration. A polyclonal antiserum was raised against the excised protein band from SDS/PAGE and purified antibodies were used for the complete purification of native cysteine-S-conjugate N-acetyltransferase by immunoaffinity chromatography. A dimeric form of the enzyme was sometimes detected on SDS/PAGE, depending on the degree of purification. For further characterization of cysteine-S-conjugate N-acetyltransferase, the stability of catalytic activity, the pH optimum and Km values were determined. The inhibitory effects of various agents were tested, revealing a substantial, yet not complete, loss of cysteine-S-conjugate N-acetyltransferase activity after treatment with cysteine proteinase inhibitors or probenecid under various conditions.
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Bakour, Meryem, Nawal Hammas, Hassan Laaroussi, Driss Ousaaid, Hinde EL Fatemi, Abderrazak Aboulghazi, Najoua Soulo, and Badiaa Lyoussi. "Moroccan Bee Bread Improves Biochemical and Histological Changes of the Brain, Liver, and Kidneys Induced by Titanium Dioxide Nanoparticles." BioMed Research International 2021 (June 23, 2021): 1–13. http://dx.doi.org/10.1155/2021/6632128.
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Titanium dioxide nanoparticles (TiO2) were used in various fields such as food industry, cosmetics, medicine, and agriculture. Despite the many advantages of nanotechnology, the adverse effects of nanoparticles are inevitable. The present study was conducted to evaluate the protective effect of bee bread on titanium dioxide (TiO2) nanoparticle toxicity. Male rats were randomly divided into four groups: Group 1 received daily by gavage (10 mL/kg bw) of distilled water, Group 2 received bee bread ethanolic extract (100 mg/kg bw), Group 3 received TiO2 (100 mg/kg bw) and distilled water (10 mL/kg bw), and Group 4 received TiO2 (100 mg/kg bw) and bee bread ethanolic extract (100 mg/kg bw). All treatments were given daily by gavage during 30 days. At the end of the experiment period, blood samples were collected to analyze fasting blood glucose, lipid profile (TC, TG, LDL-C, HDL-C, and VLDL-C), liver enzymes (AST, ALT, and LDH), total protein, urea, albumin, creatinine, sodium, potassium, and chloride ions. In addition, histological examinations of the kidneys, liver, and brain were investigated. The results showed that the subacute administration of TiO2 alone (100 mg/kg bw) had induced hyperglycemia (309 ± 5 mg/dL) and elevation of hepatic enzyme levels, accompanied by a change in both lipid profile and renal biomarkers as well as induced congestion and dilatation in the hepatic central vein and congestion in kidney and brain tissues. However, the cotreatment with bee bread extract restored these biochemical parameters and attenuated the deleterious effects of titanium nanoparticles on brain, liver, and kidney functions which could be due to its rich content on functional molecules. The findings of this paper could make an important contribution to the field of using bee bread as a detoxifying agent against titanium dioxide nanoparticles and other xenobiotics.
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Watanabe, Atsushi, Takeshi Marumo, Wakako Kawarazaki, Mitsuhiro Nishimoto, Nobuhiro Ayuzawa, Kohei Ueda, Daigoro Hirohama, et al. "Aberrant DNA methylation of pregnane X receptor underlies metabolic gene alterations in the diabetic kidney." American Journal of Physiology-Renal Physiology 314, no. 4 (April 1, 2018): F551—F560. http://dx.doi.org/10.1152/ajprenal.00390.2017.
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Epigenetic abnormalities have been suggested to mediate metabolic memory observed in diabetic complications. We have shown that epigenetic alterations may induce persistent phenotypic changes in the proximal tubules of the diabetic kidneys. In this study, we show that pregnane X receptor (PXR), a xenobiotic nuclear receptor, is epigenetically altered and upregulated and may have a possible function in the diabetic kidney. PXR has been shown to play a critical role in metabolic changes in obesity and diabetes; however, its distribution and function in the kidney are unknown. In the normal kidney, Pxr was selectively expressed in the proximal tubular cells with demethylation in the promoter DNA. In db/db mice, significant increases in Pxr mRNA, further demethylation of DNA, and stimulatory histone marks in the promoter were observed. Epigenetic changes are likely to play a causative role in PXR induction, since a DNA methyltransferase inhibitor increased PXR mRNA in cultured human proximal tubular cells. Administration of a PXR agonist increased mRNA levels of solute carrier organic anion transporter family member 2B1 ( Slco2b1), a xenobiotic transporter; response gene to complement 32 ( Rgc32), a molecule known to exert fibrotic effects in the kidney; and phosphoenolpyruvate carboxykinase 1 ( Pck1), a gluconeogenic enzyme in the kidney. The expressions of these genes were inhibited by PXR small interfering RNA in cultured proximal tubular cells. Increased mRNA levels of Slco2b1, Rgc32, and Pck1 were also observed in the kidney of db/db mice. These data indicate that PXR is upregulated in the diabetic kidney with aberrant epigenetic modifications and may modulate the course of diabetic kidney disease through the activation of these genes.
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Ghallab, Ahmed, Reham Hassan, Maiju Myllys, Wiebke Albrecht, Adrian Friebel, Stefan Hoehme, Ute Hofmann, et al. "Subcellular spatio-temporal intravital kinetics of aflatoxin B1 and ochratoxin A in liver and kidney." Archives of Toxicology 95, no. 6 (May 18, 2021): 2163–77. http://dx.doi.org/10.1007/s00204-021-03073-5.
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AbstractLocal accumulation of xenobiotics in human and animal tissues may cause adverse effects. Large differences in their concentrations may exist between individual cell types, often due to the expression of specific uptake and export carriers. Here we established a two-photon microscopy-based technique for spatio-temporal detection of the distribution of mycotoxins in intact kidneys and livers of anesthetized mice with subcellular resolution. The mycotoxins ochratoxin A (OTA, 10 mg/kg b.w.) and aflatoxin B1 (AFB1, 1.5 mg/kg b.w.), which both show blue auto-fluorescence, were analyzed after intravenous bolus injections. Within seconds after administration, OTA was filtered by glomeruli, and enriched in distal tubular epithelial cells (dTEC). A striking feature of AFB1 toxicokinetics was its very rapid uptake from sinusoidal blood into hepatocytes (t1/2 ~ 4 min) and excretion into bile canaliculi. Interestingly, AFB1 was enriched in the nuclei of hepatocytes with zonal differences in clearance. In the cytoplasm of pericentral hepatocytes, the half-life (t1/2~ 63 min) was much longer compared to periportal hepatocytes of the same lobules (t1/2 ~ 9 min). In addition, nuclear AFB1 from periportal hepatocytes cleared faster compared to the pericentral region. These local differences in AFB1 clearance may be due to the pericentral expression of cytochrome P450 enzymes that activate AFB1 to protein- and DNA-binding metabolites. In conclusion, the present study shows that large spatio-temporal concentration differences exist within the same tissues and its analysis may provide valuable additional information to conventional toxicokinetic studies.
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Owumi, Solomon E., Uche J. Dim, and Eseroghene S. Najophe. "Diethylnitrosamine aggravates cadmium-induced hepatorenal oxidative damage in prepubertal rats." Toxicology and Industrial Health 35, no. 8 (July 23, 2019): 537–47. http://dx.doi.org/10.1177/0748233719863287.
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The adverse health consequences of environmental, occupational, and dietary exposure to either diethylnitrosamine (DEN) or cadmium (Cd) have been widely investigated. However, because most environmental exposures to xenobiotics do not occur in isolation but in mixtures, the effects of simultaneous exposure to both DEN and Cd on hepatorenal function deserves investigation. The present study investigated the impact of 7 days oral co-exposure to 10 mg/kg body weight (b.w.) of DEN and 5 mg/kg b.w. of Cd on biomarkers of hepatic and renal functions, antioxidant defense systems, and oxidative stress indices in the liver and kidney of prepubertal rats. The results showed that the significant ( p < 0.05) increases in the levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma glutamyl transferase, urea, and creatinine following separate administration of DEN and Cd to rats were further increased in the co-exposure group. Moreover, marked decreases in the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase as well as glutathione levels following individual administration of DEN and Cd to rats were exacerbated in the co-exposure group. Further, the marked increase in the lipid peroxidation level and the histopathological lesions in the liver and kidney of rats treated with DEN or Cd alone were intensified in the co-exposure group These findings indicate that co-exposure to DEN and Cd elicited more severe hepatic and renal oxidative damage in the rats, thus suggesting a greater risk to humans who are co-exposed to them.
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Sinal, Christopher J., John R. Bend, Lin-Fu Zhu, Robert Zhong, and M. George Cherian. "Liver transplantation induces cytochrome P450 1A1 dependent monooxygenase activity in rat lung and kidney." Canadian Journal of Physiology and Pharmacology 73, no. 1 (January 1, 1995): 146–52. http://dx.doi.org/10.1139/y95-022.
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Although liver transplantation has been the subject of intensive investigation, comparatively little is known regarding the effects of this procedure on the metabolism of xenobiotics. The objective of the present study was to examine the effect of orthotopic liver transplantation on rat hepatic, pulmonary, and renal microsomal cytochrome P450 (P450) monooxygenase activity through the use of isozyme-selective substrates. Pulmonary microsomal P450 1A1 dependent 7-ethoxyresorufm O-deethylation (ERFD) activity increased over time in recipient rats, with maximal induction (750% of donor) observed after 21 days. Similarly, ERFD activity in renal microsomes was increased (200% of donor) after 21 days. Both pulmonary and renal microsomal P450 2B dependent 7-pentoxyresorufin O-depentylation (PRFD) activity was decreased (50 and 75% of donor) 1 day after transplantation but was essentially unchanged 3, 7, and 21 days after transplantation. Pulmonary and renal microsomal heme oxygenase activities were not significantly affected by liver transplantation. In contrast, total hepatic microsomal P450 concentrations were decreased maximally (to 45% of donor concentration) 7 days after transplantation and remained low (55% of donor) up to 21 days. Similarly, hepatic P450 1A dependent ERFD and P450 2B dependent PRFD activities were maximally depressed (20 and 25% of donor activities) after 7 days and remained low (75 and 30% of donor) up to 21 days after transplantation. The decreases in rates of hepatic P450 monooxygenation were accompanied by significant increases in microsomal heme oxygenase activity. The data presented in this study suggest the existence of generalized stress responses to inflammation that result in tissue- and isozyme-selective modulation of P450 monooxygenase activity. These responses most likely reflect complex interactions among multiple inflammatory mediators as well as perturbations in the levels of endogenous P450 substrates.Key words: cytochrome P450, orthotopic liver transplant, inflammation, heme oxygenase, lung, kidney, rat.
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Genchi, Giuseppe, Maria Stefania Sinicropi, Graziantonio Lauria, Alessia Carocci, and Alessia Catalano. "The Effects of Cadmium Toxicity." International Journal of Environmental Research and Public Health 17, no. 11 (May 26, 2020): 3782. http://dx.doi.org/10.3390/ijerph17113782.
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Cadmium (Cd) is a toxic non-essential transition metal that poses a health risk for both humans and animals. It is naturally occurring in the environment as a pollutant that is derived from agricultural and industrial sources. Exposure to cadmium primarily occurs through the ingestion of contaminated food and water and, to a significant extent, through inhalation and cigarette smoking. Cadmium accumulates in plants and animals with a long half-life of about 25–30 years. Epidemiological data suggest that occupational and environmental cadmium exposure may be related to various types of cancer, including breast, lung, prostate, nasopharynx, pancreas, and kidney cancers. It has been also demonstrated that environmental cadmium may be a risk factor for osteoporosis. The liver and kidneys are extremely sensitive to cadmium’s toxic effects. This may be due to the ability of these tissues to synthesize metallothioneins (MT), which are Cd-inducible proteins that protect the cell by tightly binding the toxic cadmium ions. The oxidative stress induced by this xenobiotic may be one of the mechanisms responsible for several liver and kidney diseases. Mitochondria damage is highly plausible given that these organelles play a crucial role in the formation of ROS (reactive oxygen species) and are known to be among the key intracellular targets for cadmium. When mitochondria become dysfunctional after exposure to Cd, they produce less energy (ATP) and more ROS. Recent studies show that cadmium induces various epigenetic changes in mammalian cells, both in vivo and in vitro, causing pathogenic risks and the development of various types of cancers. The epigenetics present themselves as chemical modifications of DNA and histones that alter the chromatin without changing the sequence of the DNA nucleotide. DNA methyltransferase, histone acetyltransferase, histone deacetylase and histone methyltransferase, and micro RNA are involved in the epigenetic changes. Recently, investigations of the capability of sunflower (Helianthus annuus L.), Indian mustard (Brassica juncea), and river red gum (Eucalyptus camaldulensis) to remove cadmium from polluted soil and water have been carried out. Moreover, nanoparticles of TiO2 and Al2O3 have been used to efficiently remove cadmium from wastewater and soil. Finally, microbial fermentation has been studied as a promising method for removing cadmium from food. This review provides an update on the effects of Cd exposure on human health, focusing on the cellular and molecular alterations involved.
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Zhang, Qi, Cong Zhang, Jing Ge, Mei-Wei Lv, Milton Talukder, Kai Guo, Yan-hua Li, and Jin-Long Li. "Ameliorative effects of resveratrol against cadmium-induced nephrotoxicity via modulating nuclear xenobiotic receptor response and PINK1/Parkin-mediated Mitophagy." Food & Function 11, no. 2 (2020): 1856–68. http://dx.doi.org/10.1039/c9fo02287b.
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Resveratrol is shown to alleviate Cd-induced histopathological lesions of the kidney, mitigating Cd-induced oxidative stress by activating NXRs (CAR/PXR/AHR/Nrf2) response and phase II detoxification system.
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Giustarini, Daniela, Federico Galvagni, Isabella Dalle-Donne, Aldo Milzani, Monica Lucattelli, Giovanna De Cunto, Desirée Bartolini, et al. "Anethole Dithiolethione Increases Glutathione in Kidney by Inhibiting γ-Glutamyltranspeptidase: Biochemical Interpretation and Pharmacological Consequences." Oxidative Medicine and Cellular Longevity 2020 (September 28, 2020): 1–13. http://dx.doi.org/10.1155/2020/3562972.
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Aims. Anethole dithiolethione (ADT) is a marketed drug to treat xerostomia. Its mechanism of action is still unknown, but several preclinical studies indicate that it is able to increase intracellular glutathione (GSH) and protect against oxidative stress. Here, we investigated the molecular mechanisms behind these effects. Results. Oral treatment of rats confirmed the GSH enhancing properties of ADT; among the different organs examined in this study, only the kidney showed a significant GSH increase that was already observed at low-dose treatments. The increase in GSH correlated with a decrease in γ-glutamyltranspeptidase (γ-GT) activity of the different tissues. In vitro and ex vivo experiments with tubular renal cells and isolated perfused rat kidney showed that the cellular uptake of intact GSH was correlated with the extracellular concentrations of GSH. Conclusions. The prominent in vivopharmacological effect of ADT was a marked increase of GSH concentration in the kidney and a decrease of some systemic and renal biomarkers of oxidative stress. In particular, by inhibition of γ-GT activity, it decreased the production cysteinylglycine, a thiol that has prooxidant effects as the consequence of its autooxidation. The activity of ADT as GSH enhancer in both the circulation and the kidney was long-lasting. All these characteristics make ADT a promising drug to protect the kidney, and in particular proximal tubule cells, from xenobiotic-induced damage.
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Rabot, Sylvie, Lionelle Nugon-Baudon, and Odette Szylit. "Alterations of the hepatic xenobiotic-metabolizing enzymes by a glucosinolate-rich diet in germ-free rats: influence of a pre-induction with phenobarbital." British Journal of Nutrition 70, no. 1 (July 1993): 347–54. http://dx.doi.org/10.1079/bjn19930127.
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Germ-free growing rats were fed on a glucosinolate-rich diet (rapeseed-meal-based) and compared with counterparts fed on a glucosinolate-free diet (soya-bean-meal-based), both diets being isonitrogenous and isoenergetic. For each diet half the animals received phenobarbital in drinking water as an inducer of xenobiotic-metabolizing enzymes. Some of the usual deleterious glucosinolate-linked effects, i.e. kidney hypertrophy and reduction in growth and feed intake, were followed and three of the major hepatic xenobiotic-metabolizing enzymes were investigated. Growth rate, dietary intake and kidney weight were not altered by glucosinolates in the absence of intestinal microflora, whether the animals were treated with phenobarbital or not. As far as the hepatic xenobiotic-metabolizing enzymes are concerned, the specific level of cytochrome P450 and the specific activities of glutathione-S-transferase (EC 2.5.1.18) and UDPglucuronosyltransferase (EC 2.4.1.17) remained unchanged in rats receiving the glucosinolate-rich diet compared with the control animals. Despite the low dose given, phenobarbital displayed its usual inducing effect on all three enzymes, similar whatever the diet. A previous counterpart experiment performed with conventional animals had shown that glucosinolate feeding led to large alterations of the variables herein studied, some of these modifications being hugely enhanced by a phenobarbital treatment. Therefore, the present results obtained on germ-free animals prove that alterations of the xenobiotic-metabolizing enzymes induced by glucosinolates are somehow mediated by the intestinal microflora. Furthermore, the involvement of those enzymes in glucosinolate toxicity definitely requires the presence of the intestinal microflora.
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Khan, Sabiha. "Endosulphan Concentration alters biomarkers in albino rat." Indian Journal of Pharmaceutical and Biological Research 2, no. 02 (June 30, 2014): 14–17. http://dx.doi.org/10.30750/ijpbr.2.2.3.
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Effect of 11.01ppm of endosulfan dose on the enzyme Acid phosphatase and Alkaline phosphatase in liver and kidney of 5 week of swiss albino rat was studied for different period of exposure. The enzyme activity increased due to congestion, biliary hindrance and hyperplasia swelling of renal tubules and vacuolization. Phosphatase testing is used to assess enzymatic damage caused by kidney disease, liver disease, or a heart attack. Primary site of organochlorine storage in the body is adipose tissue. It is metabolized in the liver as a lipophilic xenobiotic to hepatotoxic intermediates by mono-oxygenase systems which cause oxidative stress. Increase in acid phosphatase and alkaline phosphatase activity is due to leakage of lysosomal enzymes into the cytoplasm and renal necrosis and pyknotic nuclei. Endosulphan effects the biomarker of albino rat.
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Belicheva, Lidia A., and Julia N. Sharova. "Assessment of Fish Health Status Under Long-Term Water Pollution : Vygozero Reservoir , North-West Russia." Environment. Technology. Resources. Proceedings of the International Scientific and Practical Conference 2 (August 5, 2015): 368. http://dx.doi.org/10.17770/etr2011vol2.965.
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Environmental pollution and its effects on the health of aquatic ecosystems is a great problem that has been studied intensely in the last years. The Vygozero reservoir is one of the largest water bodies of the Karelian Republic. Its ecosystem has undergone significant changes since the 1930s mainly due to anthropogenic influence from the development of pulp and paper mill industry leading to accumulation of toxic contaminants and eutrophication. At present, the water body has been shown to be also polluted by hydrocarbon products and heavy metals. Among the huge changes in Vygozero ecosystem is the decrease of some fish populations and partial loose of commercial fishing importance. Despite the obvious changes in fish population the chronic biological effects of the Vygozero reservoir pollution on fish organism are poorly studied. This study is concerned with the evaluation of pollution influence on fish health status and establishment relation between fish health and environmental quality. The parameters selected for this aim were the occurrence of gills, liver and kidney alterations, as histopathological changes are widely used as biomarkers in the evaluation of the health of fish exposed to contaminants. Our findings confirm chronic pollution of the Vygozero reservoir. Histological analysis of fish tissues revealed a variety of progressive, regressive, inflammatory, circulatory disturbances and neoplastic changes. Observed histological alterations indicate that organism of fish from Vygozero reservoir responses to the impaired environment quality. Revealed histopathologies are sings of metabolic disorders, immunity suppression, compensatory reactions development and functional abnormalities in vital organs of studied fish. The results of the study correspond to the prior research devoted to ascertain tissue changes in different fish species taken from an area with chronic multiple anthropogenic impact. So it can be concluded that histopathological lesions are result of long-term effect of toxic xenobiotics.
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Dunbar, Donald R., Hiba Khaled, Louise C. Evans, Emad A. S. Al-Dujaili, Linda J. Mullins, John J. Mullins, Christopher J. Kenyon, and Matthew A. Bailey. "Transcriptional and physiological responses to chronic ACTH treatment by the mouse kidney." Physiological Genomics 40, no. 3 (February 2010): 158–66. http://dx.doi.org/10.1152/physiolgenomics.00088.2009.
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We investigated the effects on urinary steroid and electrolyte excretion and renal gene expression of chronic infusions of ACTH in the mouse. ACTH caused a sustained increase in corticosteroid excretion; aldosterone excretion was only transiently elevated. There was an increase in the excretion of deoxycorticosterone, a weak mineralocorticoid, to levels of physiological significance. Nevertheless, we observed neither antinatriuresis nor kaliuresis in ACTH-treated mice, and plasma renin activity was not suppressed. We identified no changes in expression of mineralocorticoid target genes. Water turnover was increased in chronic ACTH-treated mice, as were hematocrit and hypertonicity: volume contraction is consistent with high levels of glucocorticoid. ACTH-treated mice exhibited other signs of glucocorticoid excess, such as enhanced weight gain and involution of the thymus. We identified novel ACTH-induced changes in 1) genes involved in vitamin D ( Cyp27b1, Cyp24a1, Gc) and calcium ( Sgk, Calb1, Trpv5) metabolism associated with calciuria and phosphaturia; 2) genes that would be predicted to desensitize the kidney to glucocorticoid action ( Nr3c1, Hsd11b1, Fkbp5); and 3) genes encoding transporters of enzyme systems associated with xenobiotic metabolism and oxidative stress. Although there is evidence that ACTH-induced hypertension is a function of physiological cross talk between glucocorticoids and mineralocorticoids, the present study suggests that the major changes in electrolyte and fluid homeostasis and renal function are attributable to glucocorticoids. The calcium and organic anion metabolism pathways that are affected by ACTH may explain some of the known adverse effects associated with glucocorticoid excess.
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Rakitskii, Valery N., Tatiana M. Epishina, and Elena G. Chkhvirkiya. "Studying of the remote effects of the action on the organism of rats of the compaund from the class benzothiadiazinones." Hygiene and sanitation 99, no. 9 (October 20, 2020): 986–89. http://dx.doi.org/10.47470/0016-9900-2020-99-9-986-989.
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Introduction. Currently, many xenobiotics are widely used in industry and agriculture, which can cause serious disorders of pregnancy and fetal development. In this regard, the study of the effect of pesticides on embryogenesis in experiments on laboratory animals is a mandatory stage of sanitary and Toxicological research. The aim of the study was to investigate the long-term effects of a compound of the class of benzothiadiazinones for the assessment of embryotoxic and teratogenic effects, as well as reproductive toxicity by the method of two generations, with repeated oral intake of it into the body of warm-blooded animals (rats), establishing the levels of inactive doses for parents and offspring, and determining the hazard class. Material and methods. The embryotoxic and teratogenic effects were evaluated in female and male rats with a bodyweight of 230-240 g at the beginning of the study. Tested doses: 40.0; 100.0 and 250.0 mg / kg body weight (1 control and 3 experimental groups, 15 individuals each). Mating of females was performed with intact males in a ratio of 2:1. the Compound was introduced during 20 days of pregnancy. In the dynamics of the experiment, the state and behavior of rats, water and feed consumption, and changes in body weight were observed. The analysis of embryonic material took into account: the absolute and relative mass of internal organs (thymus, heart, lungs, liver, kidneys), to determine the teratogenic effect, a group of fruits (1/3) was fixed in Buena fluid and used to study internal organs using the Wilson method modified by Dyban the remaining 1/3 of the fetuses was fixed in ethanol to study the state of the skeleton using the Dawson method. When studying the reproductive toxicity of benzothiadiazinones in mammals (rats) using the method of two generations at doses of 15.0; 50.0 and 200.0 mg/kg of body weight (1 control and 3 experimental groups, 20 individuals each). Female F0 of the parent generation was primed during the mating period, pregnancy, and continued until the end of the feeding of the F2 generation. Mating 2:1. Results. Based on the results of studying the embryotoxic and teratogenic effects, invalid doses were established at the following levels: Noel for the mother - 100.0 mg/kg of body weight; Noel for embryotoxicity - 100.0 mg/kg of body weight; NOEL for teratogenicity-100.0 mg/kg of body weight. Results on the study of reproductive activity: NOEL for parents and offspring-50.0 mg/kg of body weight. Discussion. Studies on the effects of a long-term action of a technical product - “generic”, belonging to the class of benzothiadiazinones, found the studied compound for teratogenic, embryotoxic effects, as well as for its effect on reproductive toxicity, in accordance with the hygienic classification of pesticides by hazard (SanPiN 1.2.2584-10)to be a moderately dangerous compound (hazard class 3). Studied product class benzothiadiazinones on toxicological parameters are identical with the technical product is “originator”. Conclusion. Thus, the research shows that it is necessary to study the effects of long-term action of xenobiotics on the mammalian body when conducting sanitary and toxicological studies, to increase the reliability of the developed hygiene standards in environmental objects and food products.
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Mahringer, Anne, Alexandra Bernd, David S. Miller, and Gert Fricker. "Aryl hydrocarbon receptor ligands increase ABC transporter activity and protein expression in killifish (Fundulus heteroclitus) renal proximal tubules." Biological Chemistry 400, no. 10 (October 25, 2019): 1335–45. http://dx.doi.org/10.1515/hsz-2018-0425.
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Abstract Many widespread and persistent organic pollutants, for example, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and some polychlorinated biphenyls, activate the aryl hydrocarbon receptor (AhR) causing it to translocate to the cell nucleus where it transactivates target genes, increasing expression of a number of xenobiotic metabolizing enzymes as well as some transporters. AhR’s ability to target transporters within the kidney is essentially unexplored. We show here that exposing isolated killifish (Fundulus heteroclitus) renal proximal tubules to micromolar β-naphthoflavone (BNF) or nanomolar TCDD roughly doubled the transport activity of Multidrug resistance-associated proteins Mrp2 and Mrp4, P-glycoprotein (P-gp) and Breast cancer resistance protein (Bcrp), all ATP-driven xenobiotic efflux pumps and critical determinants of renal xenobiotic excretion. These effects were abolished by actinomycin D and cycloheximide and by the AhR antagonist, α-naphthoflavone, indicating that increased transport activity was dependent on transcription and translation as well as ligand binding to AhR. Quantitative immunostaining of renal tubules exposed to BNF and TCDD showed increased luminal membrane expression of Mrp2, Mrp4, P-gp and Bcrp. Thus, in these renal tubules, the four ABC transporters are targets of AhR action.
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Zeferino, C. P., K. D. Wells, A. S. A. M. T. Moura, R. A. Murarolli, G. E. Rottinghaus, and D. R. Ledoux. "Gene expression in the kidneys of broilers fed ochratoxin A for different time periods." World Mycotoxin Journal 9, no. 2 (March 11, 2016): 257–68. http://dx.doi.org/10.3920/wmj2014.1873.
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Consumption of ochratoxin A (OTA) contaminated diets by broilers results in economic losses to the poultry industry. This experiment evaluated the effects of quantity and time of exposure to dietary OTA on performance, organ weights, serum biochemistry, and renal gene expression of chicks. Determination of genes expressed in response to OTA will allow for the identification of pathways that are influenced by OTA. 180-day old male broiler chicks were randomly assigned to a 3×3 factorial arrangement of treatments (3 levels of OTA; 0, 1 and 2 mg OTA/kg diet and 3 time periods; 7, 14 and 21 days) with 4 replicate pens of 5 birds each per treatment. For RNA-sequencing analysis (RNA-Seq), kidney samples were collected weekly from 3 controls and 3 chicks fed 1 mg OTA/kg. NextGENe software was used for read alignment and transcript quantification. Birds fed 2 mg OTA/kg diet had decreased feed intake and body weight gain, and increased serum uric acid on days 14 and 21. Compared to controls, birds fed 2 mg OTA/kg diet also had poorer feed conversion and increased kidney weights. On day 21, birds fed 1 mg OTA/kg diet had decreased albumin, and aspartate aminotransferase concentrations. Genes associated with carbohydrate and amino acid metabolism were downregulated, and genes associated with the immune system were upregulated at days 7 and 14. Genes associated with lipid metabolism and xenobiotic biodegradation were also downregulated on day 14. These changes disappeared on day 21 suggesting that the kidney and other related organs were repaired or the damage was contained. In conclusion, decreased performance and increased kidney weight and serum uric acid in birds fed 2 mg OTA/kg confirmed the effects of OTA. Supplementation of 1 mg OTA/kg diet caused time-dependent alterations in renal gene expression in chicks.
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Mossoba, Miriam E., Thomas J. Flynn, Sanah Vohra, Paddy Wiesenfeld, and Robert L. Sprando. "Evaluation of “Dream Herb,”Calea zacatechichi, for Nephrotoxicity Using Human Kidney Proximal Tubule Cells." Journal of Toxicology 2016 (2016): 1–7. http://dx.doi.org/10.1155/2016/9794570.
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A recent surge in the use of dietary supplements, including herbal remedies, necessitates investigations into their safety profiles. “Dream herb,”Calea zacatechichi, has long been used in traditional folk medicine for a variety of purposes and is currently being marketed in the US for medicinal purposes, including diabetes treatment. Despite the inherent vulnerability of the renal system to xenobiotic toxicity, there is a lack of safety studies on the nephrotoxic potential of this herb. Additionally, the high frequency of diabetes-associated kidney disease makes safety screening ofC. zacatechichifor safety especially important. We exposed human proximal tubule HK-2 cells to increasing doses of this herb alongside known toxicant and protectant control compounds to examine potential toxicity effects ofC. zacatechichirelative to control compounds. We evaluated both cellular and mitochondrial functional changes related to toxicity of this dietary supplement and found that even at low doses evidence of cellular toxicity was significant. Moreover, these findings correlated with significantly elevated levels of nephrotoxicity biomarkers, lending further support for the need to further scrutinize the safety of this herbal dietary supplement.
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Lemaire, J., C. Van der Hauwaert, G. Savary, E. Dewaeles, M. Perrais, J. M. Lo Guidice, N. Pottier, F. Glowacki, and C. Cauffiez. "Cadmium-Induced Renal Cell Toxicity Is Associated With MicroRNA Deregulation." International Journal of Toxicology 39, no. 2 (January 14, 2020): 103–14. http://dx.doi.org/10.1177/1091581819899039.
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Cadmium is an environmental pollutant well known for its nephrotoxic effects. Nevertheless, mechanisms underlying nephrotoxicity continue to be elucidated. MicroRNAs (miRNAs) have emerged in recent years as modulators of xenobiotic-induced toxicity. In this context, our study aimed at elucidating whether miRNAs are involved in renal proximal tubular toxicity induced by cadmium exposure. We showed that cadmium exposure, in 2 distinct renal proximal tubular cell models (renal proximal tubular epithelial cell [RPTEC]/human telomerase reverse transcriptase [hTERT] and human kidney-2), resulted in cytotoxicity associated with morphological changes, overexpression of renal injury markers, and induction of apoptosis and inflammation processes. Cadmium exposure also resulted in miRNA modulation, including the significant upregulation of 38 miRNAs in RPTEC/hTERT cells. Most of these miRNAs are known to target genes whose coding proteins are involved in oxidative stress, inflammation, and apoptosis, leading to tissue remodeling. In conclusion, this study provides a list of dysregulated miRNAs which may play a role in the pathophysiology of cadmium-induced kidney damages and highlights promising cadmium molecular biomarkers that warrants to be further evaluated.
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Miranda, C. L., M. C. Henderson, J. L. Wang, H. S. Nakaue, and D. R. Buhler. "Comparative effects of the polychlorinated biphenyl mixture, aroclor 1242, on porphyrin and xenobiotic metabolism in kidney of japanese quail and rat." Comparative Biochemistry and Physiology Part C: Comparative Pharmacology 103, no. 1 (September 1992): 149–52. http://dx.doi.org/10.1016/0742-8413(92)90244-2.
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Borschovetska, Vira, and Valeriia Mamiienko. "Biochemical indicators of renal functional state under the conditions of bisphenol A administration and low-level laser irradiation." Biolohichni systemy 12, no. 2 (December 23, 2020): 180–86. http://dx.doi.org/10.31861/biosystems2020.02.180.
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Nowadays, due to the mass production of plastic products, the question of the negative impact of bisphenol A on the functioning of organs and systems is acute. However, the question of the effect of this xenobiotic on the functional state of the kidneys remains open. Currently, laser irradiation of various powers is intensively used to correct pathologies. However, its biochemical feathers of the impact on biological objects require detailed research. The work is aimed at the study of nephrotoxic effects of bisphenol A under the conditions of irradiation of animals with a diode laser. ВРА was administered per os daily for 3 days at a dose of 50 mg/kg body weight, which corresponded with LOAEL dose. Irradiation was performed for 2 min with a low-diode laser λ = 650 nm (50 mW, 1.5 J/cm2 and 12.5 mW/cm2). The functional state of the kidneys was performed based on the determination of urea and creatinine content in urine and serum. The content of primary and secondary products of the LP was determined in the kidneys. It is shown, that the administration of bisphenol A is accompanied by a decrease in urea in serum and urine, an increase in serum creatinine and a decrease in this metabolite in urine, which may indicate impaired renal and hepatic function due to the damage of this organ by contaminants due to induction lipid oxidation. This is expressed by an increase in the content of conjugated diene and TBA-active compounds in the kidneys. At the same time, under the irradiation of animals, the concentration of urea and creatinine in the serum decreases compared with the BPA group, and in the urine, these indicators increase. Such results may indicate the normalization of kidney function due to the corrective action of the laser. Thus, the introduction of BPA is accompanied by the induction of LPS processes, which leads to renal dysfunction, and irradiation of animals has a corrective effect of nephrotoxic effects of BPA.
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Atsamo, Albert Donatien, Auscar Lontsie Songmene, Mireille Flaure Metchi Donfack, Omer Bébé Ngouateu, Télesphore Benoît Nguelefack, and Théophile Dimo. "Aqueous Extract from Cinnamomum zeylanicum (Lauraceae) Stem Bark Ameliorates Gentamicin-Induced Nephrotoxicity in Rats by Modulating Oxidative Stress and Inflammatory Markers." Evidence-Based Complementary and Alternative Medicine 2021 (July 19, 2021): 1–12. http://dx.doi.org/10.1155/2021/5543889.
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Nephropathies and especially nephrotoxicity have become one of the serious causes of life-threatening conditions because of intensive exposure to xenobiotic whether by environmental pollution or by drug abuse. The present study was undertaken to assess the protective effects of Cinnamomum zeylanicum stem bark aqueous extract (AECZ) on gentamicin-induced nephrotoxicity. AECZ was prepared by maceration in water and tested orally at the doses of 200 and 400 mg/kg/day to prevent gentamicin-induced nephropathies in male Wistar rats. Gentamicin (100 mg/kg/day) was administered for 14 consecutive days by intraperitoneal route, concomitantly with AECZ or silymarin (50 mg/kg/day) used as reference drug. Animal body weight was monitored during the treatment. After the last treatment on the 14th day, animals were sacrificed. Blood was collected for the evaluation of hematological and renal function biomarkers. The homogenate of one kidney was used to assess oxidative stress markers and proinflammatory cytokines, while the other one was fixed in formaldehyde for histopathological studies. Gentamicin decreased body weight, serum total proteins, and calcium level but increased kidneys’ relative weight, serum creatinine, urea, and uric acid. Moreover, the levels of reduced glutathione, catalase, and superoxide dismutase activities were decreased, while an increase in malondialdehyde, proinflammatory cytokines (TNF-α, IL-1β, and IL-6), and nitrites was observed in the negative control group as compared to normal control. Histological analysis of the kidney revealed the presence of tubular necrosis, glomerular degeneration, and macrophage infiltration in the gentamicin-treated group. All these impairment parameters were prevented by AECZ and silymarin treatments. AECZ has a protective effect against gentamicin-induced nephrotoxicity. The antioxidant and anti-inflammatory potentials of this extract may highly contribute to its nephroprotective activity.
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Bansal, Tripta, Manu Jaggi, Roop Khar, and Sushama Talegaonkar. "Emerging Significance of Flavonoids as P-Glycoprotein Inhibitors in Cancer Chemotherapy." Journal of Pharmacy & Pharmaceutical Sciences 12, no. 1 (April 6, 2009): 46. http://dx.doi.org/10.18433/j3rc77.
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Chemotherapy forms the mainstay of cancer treatment particularly for patients who do not respond to local excision or radiation treatment. However, cancer treatment by drugs is seriously limited by P-glycoprotein (P-gp) associated multi-drug resistance (MDR) in various tumor cells. On the other hand, it is now widely recognized that P-gp also influences drug transport across various biological membranes. P-gp transporter is widely present in the luminal surface of enterocytes, biliary canalicular surface of hepatocytes, apical surface of proximal tubular cells of kidney, endothelial cells of blood brain barrier, etc. thus affecting absorption, distribution, metabolism and excretion of xenobiotics. Clinical significance of above mentioned carrier is appreciated from the fact that more than fifty percent of existing anti-cancer drugs undergo inhibitable and saturable P-gp mediated efflux. Consequently, there is an increasing trend to optimize pharmacokinetics, enhance antitumour activity and reduce systemic toxicity of existing anti-cancer drugs by inhibiting P-gp mediated transport.
Although a wide variety of P-gp inhibitors have been discovered, research efforts are underway to identify the most appropriate one. Flavonoids (polyphenolic herbal constituents) form the third generation, non-pharmaceutical category of P-gp inhibitors. The effects produced by some of these components are found to be comparable to those of well-known P-gp inhibitors verapamil and cyclosporine. Identification of effective P-gp modulator among herbal compounds have an added advantage of being safe, thereby making them ideal candidates for bioavailability enhancement, tissue-penetration (e.g. blood brain barrier (BBB)), decreasing biliary excretion and multi-drug resistance modulating agents. The dual effects, i.e. P-gp modulation and antitumor activity, of these herbal derivatives may synergistically act in cancer chemotherapy. This paper presents an overview of the investigations on the feasibility and application of flavonoids as P-gp modulators for improved efficacy of anti-cancer drugs like taxanes, anthracyclines, epipodophyllotoxins, camptothecins and vinca alkaloids. The review also focuses on flavonoid-drug interactions as well as the reversal activity of flavonoids useful against MDR. In addition, the experimental models which could be used for investigation on P-gp mediated efflux are also discussed.
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Blom, Sonja, and Lars Förlin. "Effects of PCB on xenobiotic biotransformation enzyme activities in the liver and 21-hydroxylation in the head kidney of juvenile rainbow trout." Aquatic Toxicology 39, no. 3-4 (November 1997): 215–30. http://dx.doi.org/10.1016/s0166-445x(97)00035-0.
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El-Bialy, Badr E., Neveen G. El-Boraey, Ragaa A. Hamouda, and Mohamed M. Abdel-Daim. "Comparative Protective Effects of Spirulina and Spirulina Supplemented with Thiamineagainst Sub-acute Carbon Tetrachloride Toxicity in Rats." Biomedical and Pharmacology Journal 12, no. 2 (June 1, 2019): 511–26. http://dx.doi.org/10.13005/bpj/1670.
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Carbon tetrachloride (CCl4) is used extensively as an industrial solvent and considered the best-characterized experimental animal model of xenobiotic-induced hepatic toxicity via reactive oxygen species (ROS) generation. This study was designed to evaluate the protective effects of Spirulina platensis (SP) versus Spirulina platensis supplemented with thiamine (SPt) against subacute CCl4 toxicity in rats. Rats were divided into six equal groups; Control vehicle (0.5 ml/rat 1:1 olive oil in water), SP (800 mg/kg b.wt.), SPt (800 mg/kg b.wt.), CCl4 (1ml/kg b.wt.), SP + CCl4 and SPt + CCl4. All treatments were orally and daily for a month except CCl4 was given three times weekly. CCl4 caused significant reduction in body weight gain, haemoglobin content and haematocrit percentage accompanied by leukocytosis, granulocytosis, monocytosis and lymphocytopenia. Moreover, there were significant increase in the levels of serum ALT, AST; total, direct and indirect bilirubin; urea and creatinine of CCL4- intoxicated rats. CCL4- induced significant increase of malondialdehyde levels with significant reduction of catalase activity in liver and kidney. In addition, hepatic and renal various histopathological alterations were recorded. SP and SPt ameliorated almost these changes while they couldn’t reverse the reduction of body weight gains and red blood indices. The more potent effects on measured parameters were elucidated by SPt. In conclusion SP and SPt could be used as natural antioxidant supplements to counteract the CCl4 adverse effects.
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Begum, Sumreen. "Hepatic Nuclear Factor 1 Alpha (HNF-1α) In Human Physiology and Molecular Medicine." Current Molecular Pharmacology 13, no. 1 (January 15, 2020): 50–56. http://dx.doi.org/10.2174/1874467212666190930144349.
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The transcription factors (TFs) play a crucial role in the modulation of specific gene transcription networks. One of the hepatocyte nuclear factors (HNFs) family’s member, hepatocyte nuclear factor-1α (HNF-1α) has continuously become a principal TF to control the expression of genes. It is involved in the regulation of a variety of functions in various human organs including liver, pancreas, intestine, and kidney. It regulates the expression of enzymes involved in endocrine and xenobiotic activity through various metabolite transporters located in the above organs. Its expression is also required for organ-specific cell fate determination. Despite two decades of its first identification in hepatocytes, a review of its significance was not comprehended. Here, the role of HNF-1α in the above organs at the molecular level to intimate molecular mechanisms for regulating certain gene expression whose malfunctions are attributed to the disease conditions has been specifically encouraged. Moreover, the epigenetic effects of HNF-1α have been discussed here, which could help in advanced technologies for molecular pharmacological intervention and potential clinical implications for targeted therapies. HNF-1α plays an indispensable role in several physiological mechanisms in the liver, pancreas, intestine, and kidney. Loss of its operations leads to the non-functional or abnormal functional state of each organ. Specific molecular agents or epigenetic modifying drugs that reactivate HNF-1α are the current requirements for the medications of the diseases.
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Linseman, Daniel A., Timothy J. Raczniak, C. Sidney Aaron, and James A. Bacon. "Comparative Cytotoxicity Rankings of Four Aminoglycoside Antibiotics in the Chang, SIRC and LLC-PK1 Cell Lines." Alternatives to Laboratory Animals 18, no. 1_part_1 (November 1990): 283–90. http://dx.doi.org/10.1177/026119299001800128.1.
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A series of structurally related aminoglycosides — neomycin, gentamicin, amikacin, and streptomycin — were screened for cytotoxicity in three cell lines, Chang (liver), SIRC (corneal epithelial), and LLC-PK1 (kidney). The main objectives of this study were: firstly, to determine whether the proximal tubule origin of the LLC-PK1 cell line conferred increased sensitivity to this class of xenobiotic when compared to cell lines derived from organs other than the kidney; and secondly, to determine whether any of the cell lines would rank the in vitro cytotoxic potential of the compounds in an order consistent with their in vivo toxicities. LDH leakage and cell proliferative effects (CP) were the endpoints used to measure cytotoxicity. The proximal tubule derivation of the LLC-PK1 cell line did not appear to confer significantly increased sensitivity to any of the aminoglycosides tested using LDH release and cell proliferation as endpoints of cytotoxicity. The relative cytotoxicity rankings were as follows: Chang — gentamicin>neomycin>amikacin>streptomycin (LDH), neomycin∼gentamicin∼streptomycin >amikacin (CP); SIRC — neomycin∼gentamicin∼streptomycin>amikacin (LDH and CP); and LLC-PK1 — gentamicin∼streptomycin>neomycin>amikacin (LDH), and streptomycin >neomycin>gentamicin∼amikacin (CP). The results suggest that the Chang line provides a cytotoxicity ranking consistent with in vivo nephrotoxicity data. The SIRC line ranks amikacin the least cytotoxic, but fails to discriminate between the cytotoxicities of gentamicin, neomycin and streptomycin. The LLC-PK1 cell line ranks the compounds in an order which is inconsistent with in vivo results. The LLC-PK1 cell line appears to be the most sensitive to streptomycin, which is the only agent tested that is not accumulated in the kidney in vivo. The results may reflect basal cytotoxicity, since relatively non-specific endpoints were used. Perhaps the LLC-PK1 cell line would rank the cytotoxic potential of this class of compounds more accurately if parameters which are more renal-specific were measured as endpoints.
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Vargová, M., M. Gajdová, J. Jakubovský, and L. Wsolová. "Estrogenic effects of some xenobiotics." Toxicology Letters 74 (August 1994): 90. http://dx.doi.org/10.1016/0378-4274(94)90456-1.
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Ilic, Maja, Zorica Svircev, and Vladimir Baltic. "Microcystins: Potent xenobiotics." Archive of Oncology 19, no. 3-4 (2011): 67–72. http://dx.doi.org/10.2298/aoo1104067i.
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Having in mind that exposure to low levels of microcystin in drinking water represents the health risk for people, microcystins can be observed as potent xenobiotics. The consequences of exposure to natural products of the blue-green algae, the microcystins, are numerous. Among other things, there is a possibility of development of malignant disease of colon and liver. The occurrence of the tumor is, on one side, enabled by the active transportation of microcystin for achievement of high concentration intracellularly and, on the other side, by high affinity of microcystins for serine/threonine phosphatase PP1 and PP2A after which follows their inactivation. The system, which is responsible for the active transportation of microcystin, is a family of polypeptides for transportation of organic anions (OATP). Isoforms of these carriers are distributed in one tissue, like OATP1B1 and OATP1B3, which are specific for liver or many tissues, OATP1A2 carrier, present in the liver, kidney, brain and the small intestine. The consequences of high concentration of microcystin intracellularly, binding and the inhibitions of protein phosphatase, are numerous. For the occurrence of a tumor, the changes in the nucleus are important, which are related to the gene expression changes, changes in the system for damaged DNA repair and the changes in mitosis. Mediators of these changes have their role in protein activity regulation, signal transmission in the cell, damaged DNA repair, performance of the cell cycle, apoptosis, tumor suppression, cell proliferation and differentiation. Phosphatase inhibition is observed as the strategy of development of a new group of anticancer agents. As phosphatase inhibitors, microcystins and analogs are applied, possibly having the potential to express the difference in toxicity mechanism and detoxification mechanism between the healthy and the tumor cell of liver. High expression of OATP1B1 and OATP1B3 microcystin transporters in hepatocellular carcinoma would confirm selective impact of phosphatase inhibitors to the tumor cell.
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Nohl, Hans, and Klaus Stolze. "The Effects of Xenobiotics on Erythrocytes." General Pharmacology: The Vascular System 31, no. 3 (September 1998): 343–47. http://dx.doi.org/10.1016/s0306-3623(97)00457-6.
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Gagné, François. "A Research Journal Dedicated to the Effects of Xenobiotics in Organisms." Journal of Xenobiotics 10, no. 1 (September 18, 2020): 11–13. http://dx.doi.org/10.3390/jox10010003.
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The Journal of Xenobiotics (JoX), which was initially launched in January 2011 under PAGEPress (Italy) and recently with MDPI in September 2020, is devoted to the publication of novel and scientifically sound studies in the field of xenobiotics [...]
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Karkossa, Isabel, Stefanie Raps, Martin von Bergen, and Kristin Schubert. "Systematic Review of Multi-Omics Approaches to Investigate Toxicological Effects in Macrophages." International Journal of Molecular Sciences 21, no. 24 (December 9, 2020): 9371. http://dx.doi.org/10.3390/ijms21249371.
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Insights into the modes of action (MoAs) of xenobiotics are of utmost importance for the definition of adverse outcome pathways (AOPs), which are essential for a mechanism-based risk assessment. A well-established strategy to reveal MoAs of xenobiotics is the use of omics. However, often an even more comprehensive approach is needed, which can be achieved using multi-omics. Since the immune system plays a central role in the defense against foreign substances and pathogens, with the innate immune system building a first barrier, we systematically reviewed multi-omics studies investigating the effects of xenobiotics on macrophages. Surprisingly, only nine publications were identified, combining proteomics with transcriptomics or metabolomics. We summarized pathways and single proteins, transcripts, or metabolites, which were described to be affected upon treatment with xenobiotics in the reviewed studies, thus revealing a broad range of effects. In summary, we show that macrophages are a relevant model system to investigate the toxicological effects induced by xenobiotics. Furthermore, the multi-omics approaches led to a more comprehensive overview compared to only one omics layer with slight advantages for combinations that complement each other directly, e.g., proteome and metabolome.
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Silvestroni, L., and S. Palleschi. "Effects of organochlorine xenobiotics on human spermatozoa." Chemosphere 39, no. 8 (October 1999): 1249–52. http://dx.doi.org/10.1016/s0045-6535(99)00192-7.
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FerrariKusano Bucalen, Carlos. "Effects of Xenobiotics on Total Antioxidant Capacity." Interdisciplinary Toxicology 5, no. 3 (August 1, 2012): 117–22. http://dx.doi.org/10.2478/v10102-012-0019-0.
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ABSTRACT The objective of this article was to review the effects of xenobiotics on total antioxidant capacity (TAC). Measurement of TAC is appropriate for evaluation of the total antioxidant defenses of blood, cells, and different kinds of tissues and organs. TAC is reduced by alcoholism, smoking, and exposure to radiation, herbicides, carbon monoxide, carbon tetrachloride, lead, arsenic, mercury, cadmium, aluminum, and other toxic elements. The test is also an important tool in evaluating environmental and occupational exposure.
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Procházková, J. "Analysis of the Immunotoxic Effects of Xenobiotics." Human & Experimental Toxicology 11, no. 2 (March 1992): 65–70. http://dx.doi.org/10.1177/096032719201100201.
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1 Current problems in immunotoxicology are reviewed with special attention to the sensitivity of the immune system to the effects of xenobiotics. 2 Sensitivity of target cells, route of exposure, dosage, mechanism of action and response of the immune system are discussed as the main factors responsible for the ultimate effects of drugs and chemicals. 3 The methodology of immunotoxicology is divided into two main steps: preclinical screening and the monitoring of exposed persons. 4 Conclusions are prescribed about future tasks in human immunotoxicology.
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Mohammadi, Abbas, and Massumeh Ahmadizadeh. "Effects of antioxidants on xenobiotics-induced nephrotoxicity." Journal of Renal Injury Prevention 7, no. 2 (January 8, 2018): 56–57. http://dx.doi.org/10.15171/jrip.2018.14.
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Hinson, Jack A., and Poh-Gek Forkert. "Phase II enzymes and bioactivation." Canadian Journal of Physiology and Pharmacology 73, no. 10 (October 1, 1995): 1407–13. http://dx.doi.org/10.1139/y95-196.
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A colloquium entitled Phase II enzymes and bioactivation was held during the 10th International Symposium on Microsomes and Drug Oxidations in Toronto, Ont., on July 20, 1994. This colloquium was a tribute in recognition of the contributions by Dr. James R. Gillette in advancing our understanding of drug metabolism and chemical toxicity. A major focus of the colloquium was formation of conjugates such as those with glutathione (GSH) that may not lead to detoxification but to bioactivation. The GSH conjugates may be further metabolized to reactive species that cause toxicity. The nephrotoxicity of hydroquinone and bromobenzene is mediated via quinine–glutathione conjugates, and is manifested in cellular changes, including induction of the gadd-153 and hsp-70 mRNA. The formation of GSH conjugates is also involved in the bioactivation of the vicinal dihalopropane 1,2-dibromo-3-chloropropane; cytotoxic lesions are observed in the kidney and testes. The evidence indicates that conjugation is mediated by the GSH S-transferases. The symposium also covered aspects of the importance of conjugation in the pharmacokinetics of certain drugs. Conjugation reactions including sulfation are markedly influenced by the manner in which the liver processes the drug. Characteristics such as erythrocyte binding, as in the case of acetaminophen, become limiting factors in the conjugation reactions. Conjugation reactions can lead to a different outcome, such as acquired drug resistance. Conjugation of metallothioneins with the alkylating mustard drugs melphalan and chlorambucil can lead to the formation of protein adducts. Conjugation of reactive intermediates with these small molecular weight proteins may be considered as a phase II reaction and a mechanism of detoxification. A different pathway for the metabolism of xenobiotics is catalyzed by the carboxylesterases, a family of enzymes that is involved in hydrolysis of chemical compounds, generally leading to detoxification. Three rat esterases have been purified, cloned, and characterized. Two forms, hydrolase A and hydrolase B, are present in liver microsomes in a number of species, including the human. These are also detected in extrahepatic tissues. A third esterase, hydrolase S, is found in rat liver microsomes and rat serum, and may be a serum carboxylesterase secreted from the liver. A better knowledge of esterases will advance our understanding of pharmacokinetics and mechanisms of the effects of chemicals such as phenacetin and acetaminophen, two drugs that Dr. Gillette has worked with extensively. The data presented herein reflect the new and innovative approaches that have been adopted to investigate various aspects of chemical toxicity and drug metabolism. These data also indicate that significant insights are likely to come from integrated approaches utilizing established toxicological techniques together with those from other disciplines, including molecular biology and analytical chemistry.Key words: drug metabolism, drug disposition, toxicity, conjugation.
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Berkhin, E. B. "Effect of immunostimulants on tubular secretion of xenobiotics in the kidney." Bulletin of Experimental Biology and Medicine 100, no. 5 (November 1985): 1549–51. http://dx.doi.org/10.1007/bf00836162.
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Moore, Michael N., David M. Lowe, David R. Livingstone, and David R. Dixon. "Molecular and Cellular Indices of Pollutant Effects and Their Use in Environmental Impact Assessment." Water Science and Technology 18, no. 4-5 (April 1, 1986): 223–32. http://dx.doi.org/10.2166/wst.1986.0198.
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Marine and estuarine environments receive a wide variety of contaminant chemical (xenobiotic) inputs, which must now be regarded as constituents of the natural system; these xenobiotics tend to over-load the normal physiological mechanisms for their disposal. The credit for the continued survival of organisms must be accorded to the protective mechanisms of biotransfor-mation or detoxication present in cells. These include the NADPH-dependent cytochrome P-450 monooxygenases, which metabolize toxic organic xenobiotics, metallothioneins which bind and detoxify many metals and lysosomal accumulation which sequesters many xenobiotics thus compartmentalizing them away from other cellular components. This presentation considers the development of early-warning systems based on biological responses to cell injury at the molecular, subcellular and cellular levels of organization, with particular emphasis on the use of marine mussels and periwinkles as sentinel organisms for assessing pollutant effects. Responses discussed include those of the microsomal detoxication system to organic xenobiotics, functional and structural responses of lysosomes to organic and inorganic xenobiotics, quantitative structural alterations in the cells of the digestive and reproductive systems and finally genotoxicity measured using aneuploidy and sister chromatid exchange as indices of chromosomal damage. Where possible these indices are discussed in an integrated manner.
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Neville, M. C., and C. T. Walsh. "Effects of xenobiotics on milk secretion and composition." American Journal of Clinical Nutrition 61, no. 3 (March 1, 1995): 687S—694S. http://dx.doi.org/10.1093/ajcn/61.3.687s.
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Katoh, Miki. "Effects of Xenobiotics on Drug Pharmacokinetics and Safety." YAKUGAKU ZASSHI 135, no. 10 (October 1, 2015): 1115–22. http://dx.doi.org/10.1248/yakushi.15-00187.
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Walsh, Carol T., and Margaret C. Neville. "Effects of xenobiotics on milk secretion and composition." Journal of Nutritional Biochemistry 5, no. 9 (September 1994): 418–41. http://dx.doi.org/10.1016/0955-2863(94)90076-0.
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Est�vez-Alberola, M. C., and M. P. Marco. "Immunochemical determination of xenobiotics with endocrine disrupting effects." Analytical and Bioanalytical Chemistry 378, no. 3 (February 1, 2004): 563–75. http://dx.doi.org/10.1007/s00216-003-2228-z.
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Mithaishvili, Teimuraz, René Scalla, Devi Ugrekhelidze, Benedict Tsereteli, Tinatin Sadunishvili, and George Kvesitadze. "Degradation of Aromatic Compounds in Plants Grown under Aseptic Conditions." Zeitschrift für Naturforschung C 60, no. 1-2 (February 1, 2005): 97–102. http://dx.doi.org/10.1515/znc-2005-1-218.
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The aim of the work is to investigate the ability of higher plants to absorb and detoxify environmental pollutants - aromatic compounds via aromatic ring cleavage. Transformation of 14C specifically labelled benzene derivatives, [1-6-14C]-nitrobenzene, [1-6-14C]-aniline, [1-14C]- and [7-14C]-benzoic acid, in axenic seedlings of maize (Zea mays L.), kidney bean (Phaseolus vulgaris L.), pea (Pisum sativum L.) and pumpkin (Cucurbita pepo L.) were studied. After penetration in plants, the above xenobiotics are transformed by oxidative or reductive reactions, conjugation with cell endogenous compounds, and binding to biopolymers. The initial stage of oxidative degradation consists in hydroxylation reactions. The aromatic ring can then be cleaved and degraded into organic acids of the Krebs cycle. Ring cleavage is accompanied by 14CO2 evolution. Aromatic ring cleavage in plants has thus been demonstrated for different xenobiotics carrying different substitutions on their benzene ring. Conjugation with low molecular peptides is the main pathway of aromatic xenobiotics detoxification. Peptide conjugates are formed both by the initial xenobiotics (except nitrobenzene) and by intermediate transformation products. The chemical nature of the radioactive fragment and the amino acid composition of peptides participating in conjugation were identified.