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Wang, Guangbao, Yinghui Li, Wei Sun, Zhe Wang, Daoxing Chen, Sheng Shu, Jiayi Jin, et al. "Cytochrome P450-Mediated Metabolic Characterization of a Mono-Carbonyl Curcumin Analog WZ35." Pharmacology 105, no. 1-2 (October 4, 2019): 79–89. http://dx.doi.org/10.1159/000502854.
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WZ35 is a monocarbonyl analog of curcumin, which had been proved advantage over curcumin in chemical stability and antitumor activity. However, its pharmacokinetic profile has not been determined. In the present study, an ultraperformance liquid chromatography-tandem mass spectrometry assay was developed to detect concentration of WZ35 in rat plasma. Subsequently, pharmacokinetic study showed that the oral bioavailability of WZ35 is 10.56%. Cytochrome P450 (CYP450) plays a major role in metabolizing exogenous substance. The concentration of WZ35 was sharply decreased while incubating with microsome. It’s indicated that WZ35 is a substrate of CYP450s. Molecular docking assay showed that WZ35 can combine with CYP2B6 and CYP2C9 to form much more stable complex. The lowest docking energy was generated in complex with CYP2E1. The inhibition of CYP450s by WZ35 was also evaluated. Pan inhibitions of WZ35 on rat CYP3A2, CYP2B1, CYP2C11, CYP2D1, and CYP2E1 were observed by detecting probe substrates (midazolam, bupropion, tolbutamide, dextromethorphan, chlorzoxazone) and metabolites accordingly. On an average, 80% activities of enzymes were blocked. Mechanistically, the inhibitions of WZ35 on CYP3A2, CYP2B1, CYP2E1 were in a time-dependent manner according to the results of IC50 shift assay. The collective data demonstrated that the oral bioavailability of monocarbonyl analog of curcumin has significantly improved compared to curcumin. It’s both the substrate and inhibitor of CYP450s through in a time-dependent mechanism.
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TRUONG, Nhu-Traï, Arlette MONCION, Robert BAROUKI, Philippe BEAUNE, and Isabelle de WAZIERS. "Regulatory sequence responsible for insulin destabilization of cytochrome P450 2B1 (CYP2B1) mRNA." Biochemical Journal 388, no. 1 (May 10, 2005): 227–35. http://dx.doi.org/10.1042/bj20041510.
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Diabetes has been reported to increase CYP2E1 (cytochrome P450) and CYP2B1 expression at both the mRNA and protein levels in rat livers. This increase has been attributed to mRNA stabilization and can be reversed by daily insulin treatment. In a previous study, we showed that this hormone directly down-regulates CYP2E1 and 2B1 expression through a post-transcriptional mechanism in rat hepatoma cell lines. We then aimed to identify the molecular mechanisms involved in this regulation. We first identified a 16-mer sequence that we later showed to be the actual functional target of insulin on the rat CYP2E1 mRNA. Similar work was performed with CYP2B1. We first investigated the presence of mRNA–protein interactions. Using cytoplasmic proteins of Fao cells treated or not with insulin (0.1 μM) and the full-length CYP2B1 mRNA as a probe, a major CYP2B1 RNA–protein complex was observed with RNase T1 protection experiments. With the use of different CYP2B1 mRNA probes and by means of competition experiments with antisense oligonucleotides, a protein fixation site was located on a 16-nt sequence in the 5′ part of the coding region. This sequence has a hairpin loop structure, shows 80% sequence identity with a structure previously identified on CYP2E1 and is also responsible for the post-transcriptional effects of insulin on this mRNA. Protein(s) bound to both CYP2B1 and CYP2E1 sequences are cytosolic and have an apparent molecular mass of 60 kDa. The protein(s) that bind(s) to both these sequences and the insulin transduction signal involved in this regulation remain(s) to identified.
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Ferdouse, Afroza, Rishi R. Agrawal, Madeleine A. Gao, Hongfeng Jiang, William S. Blaner, and Robin D. Clugston. "Alcohol induced hepatic retinoid depletion is associated with the induction of multiple retinoid catabolizing cytochrome P450 enzymes." PLOS ONE 17, no. 1 (January 14, 2022): e0261675. http://dx.doi.org/10.1371/journal.pone.0261675.
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Chronic alcohol consumption leads to a spectrum of liver disease that is associated with significant global mortality and morbidity. Alcohol is known to deplete hepatic vitamin A content, which has been linked to the pathogenesis of alcoholic liver disease. It has been suggested that induction of Cytochrome P450 2E1 (CYP2E1) contributes to alcohol-induced hepatic vitamin A depletion, but the possible contributions of other retinoid-catabolizing CYPs have not been well studied. The main objective of this study was to better understand alcohol-induced hepatic vitamin A depletion and test the hypothesis that alcohol-induced depletion of hepatic vitamin A is due to CYP-mediated oxidative catabolism. This hypothesis was tested in a mouse model of chronic alcohol consumption, including wild type and Cyp2e1 -/- mice. Our results show that chronic alcohol consumption is associated with decreased levels of hepatic retinol, retinyl esters, and retinoic acid. Moreover, the depletion of hepatic retinoid is associated with the induction of multiple retinoid catabolizing CYPs, including CYP26A1, and CYP26B1 in alcohol fed wild type mice. In Cyp2e1 -/- mice, alcohol-induced retinol decline is blunted but retinyl esters undergo a change in their acyl composition and decline upon alcohol exposure like WT mice. In conclusion, the alcohol induced decline in hepatic vitamin A content is associated with increased expression of multiple retinoid-catabolizing CYPs, including the retinoic acid specific hydroxylases CYP26A1 and CYP26B1.
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Н.Н., Климкович,, Руденкова, Т.В., Костюк, С.А., Алешкевич, С.Н., Демиденко, А.Н., and Яковлева, Е.А. "Genetic Polymorphisms of Cytochrome P450 in Children with Acute Lymphoblastic Leukemia." Гематология. Трансфузиология. Восточная Европа, no. 4 (December 28, 2022): 418–29. http://dx.doi.org/10.34883/pi.2022.8.4.005.
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Цель. Анализ полиморфизмов генов CYP1A1, CYP2E1, CYP2D6 у детей с токсическими осложнениями на фоне лечения ОЛЛ. Материалы и методы. Материал исследования – периферическая кровь и буккальный эпителий 43 пациентов с ОЛЛ на фоне полихимиотерапии в возрасте от 2 до 17 лет. Использованы клинико-лабораторные, молекулярно-биологические (полимеразная цепная реакция (ПЦР), рестрикция фрагментов ДНК, электрофоретический анализ фрагментов ДНК), статистические методы. Результаты. Профиль токсических осложнений у детей с острыми лимфобластными лейкозами из В-клеток-предшественников на фоне химиотерапии, соответствующих III–IV степени токсичности, представлен гематологическими, гастроинтестинальными, печеночнымии и инфекционными осложнениями. Частота аллелей дикого типа была доминирующей для полиморфизмов: A4889G (rs1048943) в гене CYP1A1; T7632A (rs6413432), G1293C (rs3813867) и C1053T (rs2031920) в гене CYP2Е1; A2549del (rs35742686) в гене CYP2D6, для данных геновариантов частота выявления составила от 90,70 до 100%. Распространенность гетерозиготных геновариантов среди обследованных пациентов была выше для полиморфизма T6235C (rs4646903) в гене CYP1A1 (гетерозиготный аллель ТС – 27,91%), а также для полиморфизма G1846A (rs3892097) в гене CYP2D6 (гетерозиготный аллель GA – 32,56%). Самая высокая частота выявления мутантного аллеля была определена для полиморфизма C100T (rs1065852) в гене CYP2D6 (мутантный аллель ТТ – 27,50%). Заключение. Установлена частота выявления различных вариантов генов CYP1A1, CYP2E1, CYP2D6 у детей на фоне химиотерапии ОЛЛ. Полученные результаты лягут в основу дальнейших исследований определения ассоциации полиморфных вариантов геновCYP с формированием осложнений в ходе лечения детей с ОЛЛ. Purpose. Analysis of CYP1A1, CYP2E1, CYP2D6 gene polymorphisms in children with toxic complications during acute lymphoblastic leukemia (ALL) treatment. Materials and methods. The study material was peripheral blood and buccal epithelium of 43 patients with ALL and polychemotherapy aged from 2 to 17 years. Clinical-laboratory, molecular-biological (polymerase chain reaction (PCR), restriction of DNA fragments, electrophoretic analysis of DNA fragments), statistical methods were used. Results. The profile of toxic complications in children with ALL from B-cell precursors against during of chemotherapy, corresponding to III–IV degrees of toxicity, was represented by hematological, gastrointestinal, hepatic and infectious complications. The frequency of wild-type alleles was dominant for the polymorphisms: A4889G (rs1048943) in the CYP1A1 gene; T7632A (rs6413432), G1293C (rs3813867), and C1053T (rs2031920) in the CYP2E1 gene; A2549del (rs35742686) in the CYP2D6 gene; for these gene variants the detection rate was 90.70 to 100%. The prevalence of heterozygous gene variants among the examined patients was higher for the polymorphism T6235C (rs4646903) in the CYP1A1 gene (heterozygous allele TC – 27.91%), and for the polymorphism G1846A (rs3892097) in the CYP2D6 gene (heterozygous allele GA – 32.56%). The highest frequency of mutant allele detection was determined for the C100T polymorphism (rs1065852) in the CYP2D6 gene (mutant TT allele – 27.50%). Conclusion. The frequency of detection of different variants of CYP1A1, CYP2E1, CYP2D6 genes was established in children during of chemotherapy for ALL. The results obtained will form the basis for further studies to determine the association of CYP polymorphic variants with the formation of complications during the treatment of children with ALL.
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Kochetova, Olga V., Tatyana V. Victorova, and Lilya K. Karimova. "The roles of genes of ksenobiotics biotransformation in the development of predisposition to the toxic heoatitis in workers workers exposed to hepthyle and ethylebenzene-styrene." Ecological genetics 3, no. 1 (March 15, 2005): 3–10. http://dx.doi.org/10.17816/ecogen313-10.
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Introduction: The aim of this study was to estimate the predisposition of influencing possible factors causing chemical induced abnormal liver function on the basis of studying genes encoding xenobiotic metabolizing enzymes. Methods: Genotyping of CYP1A1, CYP2D6, CYP2E1, EPHX1, NAT2 was performed using polymerase chain reaction and restriction fragment length polymorphism on peripheral leucocyte DNA from 73 incident cases of toxic hepatitis, 163 «groups of risk» on development of a toxic hepatitis, 94 healthy workers and 335 controls.Results and conclusions: No significant association was found between a reference group and petrochemical workers when CYP1A1, CYP2D6, CYP2E1, EPHX1 genotypes were included in the analyses. Among workers was observed the increasing of frequency of a combination *4/*4 genes NAT2 compared with control group. Among the patients with a professional toxic hepatitis are established genetic markers of predisposition to development the disease: Ile/Val gene CYP1A1, Tyr/His gene EPHX1; combinations *4/*7 genes NAT2; and as slow phenotype microsomal epoxide hydrolase; combinations of genotypes IleVal/C1C1 of genes CYP1A1 and CYP2E1; combinations of slow phenotypes microsomal epoxide hydrolase and N-acetyltransferase-2. Our results suggest that genotype Ile/Ile of gene CYP1A1; genotype Tyr/Tyr of gene EPHX1; and as a normal phenotype microsomal epoxide hydrolase; a combination of genotypes IleIle/C1C1 of genes CYP1A1 and CYP2E1; a combination of genotypes IleIle/C1C1/CC/N of genes CYP1A1, CYP2E1, CYP2D6 and a normal phenotype microsomal epoxide hydrolase are protective variants. This study demonstrates a significant combined effect of phase I and phase II polymorphisms on the predisposition of professional pathology at workers exposed to hepthyle and ethylebenzene-styrene.
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Li, Xiangyang, Jianxin Yang, Yijie Qiao, Yabin Duan, Yuanyao Xin, Yongqiong Nian, Lin Zhu, and Guiqin Liu. "Effects of Radiation on Drug Metabolism: A Review." Current Drug Metabolism 20, no. 5 (June 20, 2019): 350–60. http://dx.doi.org/10.2174/1389200220666190405171303.
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Background: Radiation is the fourth most prevalent type of pollution following the water, air and noise pollution. It can adversely affect normal bodily functions. Radiation alters the protein and mRNA expression of drugmetabolizing enzymes and drug transporters and the pharmacokinetic characteristics of drugs, thereby affecting drug absorption, distribution, metabolism, and excretion. Therefore, it is important to study the pharmacokinetic changes in drugs under radiation. Methods: To update data on the effects of ionizing radiation and non-ionizing radiation caused by environmental pollution or clinical treatments on the protein and mRNA expression of drug-metabolizing enzymes and drug transporters. Data and information on pharmacokinetic changes in drugs under radiation were analyzed and summarized. Results: The effect of radiation on cytochrome P450 is still a subject of debate. The widespread belief is that higherdose radiation increased the expression of CYP1A1 and CYP1B1 of rat, zebrafish or human, CYP1A2, CYP2B1, and CYP3A1 of rat, and CYP2E1 of mouse or rat, and decreased that of rat’s CYP2C11 and CYP2D1. Radiation increased the expression of multidrug resistance protein, multidrug resistance-associated protein, and breast cancer resistance protein. The metabolism of some drugs, as well as the clearance, increased during concurrent chemoradiation therapy, whereas the half-life, mean residence time, and area under the curve decreased. Changes in the expression of cytochrome P450 and drug transporters were consistent with the changes in the pharmacokinetics of some drugs under radiation. Conclusion: The findings of this review indicated that radiation caused by environmental pollution or clinical treatments can alter the pharmacokinetic characteristics of drugs. Thus, the pharmacokinetics of drugs should be rechecked and the optimal dose should be re-evaluated after radiation.
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Shayakhmetova, G. "COMPARATIVE INVESTIGATION OF ANTI-TUBERCULOSIS DRUGS EFFECTS ON TESTICULAR CYP2Е1 EXPRESSION AND MALE REPRODUCTIVE PARAMETERS UNDER SEPARATE AND COMBINED ADMINISTRATION IN MALE RATS." Bulletin of Taras Shevchenko National University of Kyiv. Series: Biology 72, no. 2 (2016): 80–85. http://dx.doi.org/10.17721/1728_2748.2016.72.80-85.
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Comparative study of anti-tuberculosis drugs anti-androgenic effects and effects on testicular CYP2E1 has been performed. Testicular CYP2E1 mRNA and protein expression, serum total testosterone level, fertility and spermatogenesis parameters in male rats under simultaneous and separate administration of ethambutol, isoniazid, rifampin and pyrazinamide have been investigated. Analysis of the obtained data has proved the prominent role of ethambutol and isoniazid in gonadal toxicity of antituberculosis drugs combination. Activation of CYP2Е1-dependent metabolizing systems in testicular steroidogenic cells could stipulate at least a part of ethambutol, isoniazid and anti-tuberculosis drugs combination negative effects on testosterone level and spermatogenesis processes. Mechanisms of spermatogenesis alteration by rifampin and pyrazinamide need to be explored more extensively, but in the light of our observations they do not depend from testicular CYP2E1.
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ZHUKOV, Andrei, and Magnus INGELMAN-SUNDBERG. "Relationship between cytochrome P450 catalytic cycling and stability: fast degradation of ethanol-inducible cytochrome P450 2E1 (CYP2E1) in hepatoma cells is abolished by inactivation of its electron donor NADPH–cytochrome P450 reductase." Biochemical Journal 340, no. 2 (May 25, 1999): 453–58. http://dx.doi.org/10.1042/bj3400453.
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Ethanol-inducible cytochrome P450 2E1 (CYP2E1) involved in the metabolism of gluconeogenetic precursors and some cytotoxins is distinguished from other cytochrome P450 enzymes by its rapid turnover (in vivo half-life of 4-7 h), with ligands to the haem iron, both substrates and inhibitors, stabilizing the protein. CYP2E1 is also known to have a high oxidase activity in the absence of substrate, resulting in the production of reactive oxygen radicals. We suggested that the rapid intracellular turnover of the enzyme may be partly due to covalent modifications by such radicals or to other changes during catalytic cycling, in which case the inhibition of electron supply from NADPH-cytochrome P450 reductase would be expected to stabilize the protein. Fao hepatoma cells, where CYP2E1 showed a half-life of 4 h upon serum withdrawal, were treated for 1 h with 0.3 μM diphenylene iodonium (DPI), a suicide inhibitor of flavoenzymes, which resulted in ≈ 90% inhibition of the microsomal NADPH-cytochrome P450 reductase and CYP2E1-dependent chlorzoxazone hydroxylase activities. Subsequent cycloheximide chase revealed that the CYP2E1 half-life increased to 26 h. Neither the degradation rates of total protein, CYP2B1 and NADPH-cytochrome P450 reductase nor the cellular ATP level were affected by DPI under the conditions employed. These results demonstrate for the first time that the short half-life of CYP2E1 in vivo may be largely due to the rapid destabilization of the enzyme during catalytic cycling rather than to the intrinsic instability of the protein molecule.
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Shahriary, Ghazaleh Mohammadzadeh, Hamid Galehdari, Amir Jalali, Fatemeh Zanganeh, Seyed Mohammad Reza Alavi, and Mohammad Reza Aghanoori. "CYP2E1*5B, CYP2E1*6, CYP2E1*7B, CYP2E1*2, and CYP2E1*3 Allele Frequencies in Iranian Populations." Asian Pacific Journal of Cancer Prevention 13, no. 12 (December 31, 2012): 6505–10. http://dx.doi.org/10.7314/apjcp.2012.13.12.6505.
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Liu, Lingyu, Janak L. Pathak, Yong-qiang Zhu, and Matthias Bureik. "Comparison of cytochrome P450 expression in four different human osteoblast models." Biological Chemistry 398, no. 12 (November 27, 2017): 1327–34. http://dx.doi.org/10.1515/hsz-2017-0205.
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AbstractCytochromes P450 (CYPs) are important for bone homeostasis, but only limited information is available on their expression in human bone cells. We analyzed the expression levels of eight CYPs in osteoblasts cultured in human bone pieces, in osteoblasts differentiated from human periosteum mesenchymal stem cells, in primary human osteoblasts and in the human osteoblast cell line MG63, respectively. Our results confirm previous reports about the presence of CYP11A1, CYP17A1, CYP24A1 and CYP27B1, while demonstrating expression of CYP2E1, CYP26A1, CYP39A1 and CYP51A1 for the first time. However, expression patterns in the four models were remarkably different from each other.
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Sato, Yoshinori, Wenjing Dong, Tatsuro Nakamura, Naohiro Mizoguchi, Tasuku Nawaji, Miyu Nishikawa, Takenori Onaga, Shinichi Ikushiro, Makoto Kobayashi, and Hiroki Teraoka. "Transgenic Zebrafish Expressing Rat Cytochrome P450 2E1 (CYP2E1): Augmentation of Acetaminophen-Induced Toxicity in the Liver and Retina." International Journal of Molecular Sciences 24, no. 4 (February 16, 2023): 4013. http://dx.doi.org/10.3390/ijms24044013.
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Metabolic activation is the primary cause of chemical toxicity including hepatotoxicity. Cytochrome P450 2E (CYP2E) is involved in this process for many hepatotoxicants, including acetaminophen (APAP), one of the most common analgesics and antipyretics. Although the zebrafish is now used as a model for toxicology and toxicity tests, the CYP2E homologue in zebrafish has not been identified yet. In this study, we prepared transgenic zebrafish embryos/larvae expressing rat CYP2E1 and enhanced green fluorescent protein (EGFP) using a β-actin promoter. Rat CYP2E1 activity was confirmed by the fluorescence of 7-hydroxycoumarin (7-HC), a metabolite of 7-methoxycoumarin that was specific for CYP2 in transgenic larvae with EGFP fluorescence (EGFP [+]) but not in transgenic larvae without EGFP fluorescence (EGFP [−]). APAP (2.5 mM) caused reduction in the size of the retina in EGFP [+] larvae but not in EGFP [−] larvae, while APAP similarly reduced pigmentation in both larvae. APAP at even 1 mM reduced the liver size in EGFP [+] larvae but not in EGFP [−] larvae. APAP-induced reduction of liver size was inhibited by N-acetylcysteine. These results suggest that rat CYP2E1 is involved in some APAP-induced toxicological endpoints in the retina and liver but not in melanogenesis of the developing zebrafish.
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Bořek-Dohalská, Lucie, Ivan Gut, Pavel Souček, Zdeněk Roth, and Petr Hodek. "Cytochromes P450 Involved in Cyclophosphamide, Paclitaxel and Docetaxel Metabolism in Rats." Collection of Czechoslovak Chemical Communications 65, no. 7 (2000): 1183–90. http://dx.doi.org/10.1135/cccc20001183.
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We investigated involvement of cytochromes P450 (CYPs) of rat liver microsomes in metabolism of two anticancer drugs, paclitaxel (PCT) and docetaxel (DTX), by an indirect method. This method is based on the presumption that the compound competitively inhibiting oxidation of the CYP-selective substrate should also be a substrate for the CYP enzyme. The validity of this approach was confirmed using the model drug, cyclophosphamide (CPA). Indeed, CPA competitively inhibited oxidation of substrates specific for CYP2B1 and CYP3A1/2, enzymes previously reported to be capable of metabolizing CPA. Using this method, we identified CYP enzymes participating in PCT and DTX metabolism. The CYP2D1/2/3 and CYP3A1/2 are enzymes oxidizing PCT while CYP3A1/2 and CYP2E1 are responsible for metabolism of DTX. Here, we report a suitable method serving for easy and fast estimation of CYP enzymes involved in drug metabolism.
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Czekaj, P., A. Wiaderkiewicz, A. Palasz, and R. Wiaderkiewicz. "571 Pulmonary CYP1A1, CYP2B1/2, CYP2E1 and CYP3A1/2 expressions in old male rats." Toxicology Letters 144 (September 2003): s153. http://dx.doi.org/10.1016/s0378-4274(03)90570-4.
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Xu, Shang-Fu, An-Ling Hu, Lu Xie, Jia-Jia Liu, Qin Wu, and Jie Liu. "Age-associated changes of cytochrome P450 and related phase-2 gene/proteins in livers of rats." PeerJ 7 (August 2, 2019): e7429. http://dx.doi.org/10.7717/peerj.7429.
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Cytochrome P450s (CYPs) are phase-I metabolic enzymes playing important roles in drug metabolism, dietary chemicals and endogenous molecules. Age is a key factor influencing P450s expression. Thus, age-related changes of CYP 1–4 families and bile acid homeostasis-related CYPs, the corresponding nuclear receptors and a few phase-II genes were examined. Livers from male Sprague-Dawley rats at fetus (−2 d), neonates (1, 7, and 14 d), weanling (21 d), puberty (28 and 35 d), adulthood (60 and 180 d), and aging (540 and 800 d) were collected and subjected to qPCR analysis. Liver proteins from 14, 28, 60, 180, 540 and 800 days of age were also extracted for selected protein analysis by western blot. In general, there were three patterns of their expression: Some of the drug-metabolizing enzymes and related nuclear receptors were low in fetal and neonatal stage, increased with liver maturation and decreased quickly at aging (AhR, Cyp1a1, Cyp2b1, Cyp2b2, Cyp3a1, Cyp3a2, Ugt1a2); the majority of P450s (Cyp1a2, Cyp2c6, Cyp2c11, Cyp2d2, Cyp2e1, CAR, PXR, FXR, Cyp7a1, Cyp7b1. Cyp8b1, Cyp27a1, Ugt1a1, Sult1a1, Sult1a2) maintained relatively high levels throughout the adulthood, and decreased at 800 days of age; and some had an early peak between 7 and 14 days (CAR, PXR, PPARα, Cyp4a1, Ugt1a2). The protein expression of CYP1A2, CYP2B1, CYP2E1, CYP3A1, CYP4A1, and CYP7A1 corresponded the trend of mRNA changes. In summary, this study characterized three expression patterns of 16 CYPs, five nuclear receptors, and four phase-II genes during development and aging in rat liver, adding to our understanding of age-related CYP expression changes and age-related disorders.
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Gonzalez, Frank J. "CYP2E1." Drug Metabolism and Disposition 35, no. 1 (October 4, 2006): 1–8. http://dx.doi.org/10.1124/dmd.106.012492.
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Davydova, Nadezhda Y., Bikash Dangi, Marc A. Maldonado, Nikita E. Vavilov, Victor G. Zgoda, and Dmitri R. Davydov. "Toward a systems approach to cytochrome P450 ensemble: interactions of CYP2E1 with other P450 species and their impact on CYP1A2." Biochemical Journal 476, no. 23 (December 12, 2019): 3661–85. http://dx.doi.org/10.1042/bcj20190532.
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In this study, we investigate the ability of ethanol-inducible CYP2E1 to interact with other cytochrome P450 species and affect the metabolism of their substrates. As a model system, we used CYP2E1-enriched human liver microsomes (HLM) obtained by the incorporation of purified CYP2E1. Using a technique based on homo-FRET in oligomers of CYP2E1 labeled with BODIPY 577/618 maleimide we demonstrated that the interactions of CYP2E1 with HLM result in the formation of its mixed oligomers with other P450 species present in the microsomal membrane. Incorporation of CYP2E1 results in a multifold increase in the rate of metabolism of CYP2E1-specific substrates p-Nitrophenol and Chlorzaxozone. The rate of their oxidation remains proportional to the amount of incorporated CYP2E1 up to the content of 0.3–0.4 nmol/mg protein (or ∼50% CYP2E1 in the P450 pool). The incorporated CYP2E1 becomes a fully functional member of the P450 ensemble and do not exhibit any detectable functional differences with the endogenous CYP2E1. Enrichment of HLM with CYP2E1 results in pronounced changes in the metabolism of 7-ethoxy-4-cyanocoumarin (CEC), the substrate of CYP2C19 and CYP1A2 suggesting an increase in the involvement of the latter in its metabolism. This effect goes together with an augmentation of the rate of dealkylation of CYP1A2-specific substrate 7-ethoxyresorufin. Furthermore, probing the interactions of CYP2E1 with model microsomes containing individual P450 enzymes we found that CYP2E1 efficiently interacts with CYP1A2, but lacks any ability to form complexes with CYP2C19. This finding goes inline with CYP2E1-induced redirection of the main route of CEC metabolism from CYP2C19 to CYP1A2.
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Beristain-Castillo, Evelyn, Mariano Martínez-Vázquez, Rafael Camacho-Carranza, and Javier J. Espinosa-Aguirre. "CYP1A1 and Cnr nitroreductase bioactivated niclosamide in vitro." Mutagenesis 28, no. 6 (August 16, 2013): 645–51. http://dx.doi.org/10.1093/mutage/get043.
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Abstract Niclosamide produces genotoxic effects, such as point mutations in Salmonella sp., sperm-head abnormalities in mice and clastogenic effects in human lymphocytes in vitro and in vivo. As cytochrome P450 could be involved in the bioactivation of niclosamide, we investigated which subfamily was involved. We used liver microsomal fractions from rats treated with phenobarbital/β-naphthoflavone (PB/β-NF), benzo[a]pyrene (BaP) or cyclohexanol, which are known to induce different cytochrome P450 subfamilies, such as CYP2B, CYP1A1, CYP1A2 and CYP2E1. We also inhibited CYP1A and CYP2E using α-NF and diethyldithiocarbamate to identify the cytochrome P450 involved. Liver-S9 fractions obtained from PB/β-NF- and BaP-treated rats significantly increased the number of revertants induced by niclosamide, while the CYP1A1 inhibitor α-NF decreased the number of revertants. The incubation of niclosamide with CYP1A1 Supersomes™ increased the number of revertants, suggesting that CYP1A1 is responsible for the bioactivation of niclosamide. Nitroreduction is also involved in niclosamide bioactivation, as the nitroreductase-deficient strain YG7132 did not respond to the niclosamide treatment. Our findings indicated that a metabolite, derived from the action of CYP1A1 and a nitroreduction-reaction process, has a key role in the bioactivation of niclosamide.
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Самгина, Т. А., П. М. Назаренко, А. В. Полоников, and В. А. Лазаренко. "Значение однонуклеотидного полиморфизма некоторых генов системы биотрансформации ксенобиотиков в развитии острого панкреатита." Phylogenetic Analysis, no. 1;2020 (February 15, 2020): 36–41. http://dx.doi.org/10.24075/vrgmu.2020.008.
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Генетически детерминированные особенности функционирования системы биотрансформации ксенобиотиков играют важную роль в развитии острого панкреатита (ОП) и его осложнений. Целью работы было определить вклад однонуклеотидных полиморфизмов генов CYP1A1 -462 T>C rs1048943, CYP2E1 -1293 G>C rs3813867 и ABCB1 -3435 G>A rs1045642 в развитие ОП и его осложнений. Образцы ДНК получали от 547 неродственных больных ОП (154 женщины и 393 мужчины; средний возраст составил 48,9 ± 13,1), находившихся на стационарном лечении в хирургических отделениях города Курска и 573 неродственных индивида без заболеваний ЖКТ (161 женщина и 412 мужчин; средний возраст — 47,8 ± 12,1). Генотипирование полиморфизма изучаемых генов выполняли методом ПЦР путем дискриминации аллелей с помощью TaqMan-зондов. У 97 пациентов развился инфицированный панкреонекроз (ИП), у 101 — псевдокиста (ПК), у 111 — гнойно-некротический перипанкреатит (ГНП). Установлено, что у носителей аллеля А гена ABCB1 G>A (rs1045642) чаще развивался ОП (p = 0,0008), у носителей генотипа G/G редко развивался как ОП (p = 5·10–4), так и его осложнения: ИП (p = 0,03R), ГНП (p = 0,036R), ПК (p = 0,04R). Отсутствие длительного злоупотребления алкогольными напитками у носителей генотипов G/C–C/C CYP2E1 G>C (rs3813867) редко приводило к развитию ОП (p = 0,03), у носителей генотипа G/C CYP2E1 (rs3813867) (p = 0,05OD) чаще возникала псевдокиста. У носителей генотипа C/C CYP1A1 T>C (rs1048943) ОП чаще осложнялся ИП (p = 0,009R), ГНП (p = 0,003R), ПК (p = 0,003D). В целом, для носителей генотипов G/G ABCB1 G>A (rs1045642) было характерно более легкое течение ОП, тяжелое течение было характерно для носителей C/C CYP1A1 T>C (rs1048943).
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Lavandera, Jimena, Silvina Ruspini, Alcira Batlle, and Ana María Buzaleh. "Cytochrome P450 expression in mouse brain: specific isoenzymes involved in Phase I metabolizing system of porphyrinogenic agents in both microsomes and mitochondria." Biochemistry and Cell Biology 93, no. 1 (February 2015): 102–7. http://dx.doi.org/10.1139/bcb-2014-0088.
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Brain cytochrome P450 (CYP) metabolizes a variety of drugs to produce their pharmacological effects within the brain. We have previously observed that porphyrinogenic agents altered CYP levels in brain. The aim of this work was to further study the involvement of mice brain mitochondrial and microsomal Phase I drug metabolizing system when porphyrinogenic agents, such as Enflurane, Isoflurane, allylisopropylacetamide, veronal, ethanol, and Griseofulvin were administered. To this end, CYP2E1, CYP2B1, and CYP3A4 expression were measured. NADPH cytochrome P450 reductase (CPR) expression was also determined. Western Blots were performed in microsomes and mitochondria of whole brain. Some of the drugs studied altered expression mainly in microsomes. Chronic Isoflurane augmented mitochondrial isoform, although this anaesthetic diminished microsomal expression. Ethanol and topical Griseofulvin affected expression in microsomes but not in mitochondria. CYP2E1 mitochondrial activity was induced by acute Enflurane; while the activity of the microsomal protein was enhanced in alcoholised animals. Ethanol also induced CYP2E1 expression in microsomes, although Isoflurane provoked opposite effects in mitochondria and microsomes. Expression of CPR was also induced. Several reports support an emergent role of CYP enzymes in the pathogenesis of neurological disorders, so CYP response in brain could be one of the multiples factors influencing porphyria acute attacks.
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Freeman, J. E., D. Stirling, A. L. Russell, and C. R. Wolf. "cDNA sequence, deduced amino acid sequence, predicted gene structure and chemical regulation of mouse Cyp2e1." Biochemical Journal 281, no. 3 (February 1, 1992): 689–95. http://dx.doi.org/10.1042/bj2810689.
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The cDNA encoding the mouse Cyp2e1 protein has been isolated and sequenced, and shown to share 92%, 79%, 80% and 79% sequence similarity over the coding region with rat, human, rabbit 1 and rabbit 2 CYP2E1 cDNA sequences respectively. The predicted Cyp2e1 protein contains 493 amino acids, with a molecular mass of 56781 Da. The protein contains many features common to other cytochrome P450s, including a potentially phosphorylatable serine residue at position 129 within a canonical cyclic AMP-dependent protein kinase site. Southern blot analysis of genomic DNA prepared from C57BL/6 and DBA/2N mice suggests the presence of only a single Cyp2e1 gene. The Cyp2e1 gene was isolated and its organization was established by PCR using oligonucleotides to its predicted intron/exon boundaries. These results showed that the mouse Cyp2e1 gene is approx. 11,000 bp in length and has a similar structure to the human and rat CYP2E1 genes. Cyp2e1 protein expression was studied in a variety of tissues and a sexual dimorphism in its levels in some tissues was noted. Acetone treatment induced the Cyp2e1 protein in all of the tissues studied in both sexes, but this Cyp2e1 protein induction was not accompanied by an increase in Cyp2e1 mRNA levels. Indeed, mRNA levels were seen to be decreased on treatment, suggesting that acetone administration affects either mRNA translation efficiency or protein stability. Of a wide range of drugs known to modify other cytochrome P450 levels only diethylnitrosamine had a significant effect on Cyp2e1, causing a decrease in protein levels.
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Chen, Keguang, Ruichen Guo, and Chunmin Wei. "Synonymous mutation rs2515641 affects CYP2E1 mRNA and protein expression and susceptibility to drug-induced liver injury." Pharmacogenomics 21, no. 7 (May 2020): 459–70. http://dx.doi.org/10.2217/pgs-2019-0151.
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Aim: To evaluate whether the synonymous mutant rs2515641 could affect cytochrome P450 2E1 ( CYP2E1) expression and the response to acetaminophen (APAP) or triptolide (TP) treatment. Materials & methods: HepG2 cells were transfected with lentiviral vector containing either CYP2E1-1263C or CYP2E1-1263T. Some of these recombinant cells were then treated with APAP or TP. CYP2E1 gene expression was detected by PCR and western blot. Results: CYP2E1 gene expression decreased significantly both in mRNA and protein level after rs2515641 mutation, indicating that this polymorphism can affect both transcription and translation. Furthermore, rs2515641 mutation dramatically changes the response of CYP2E1 expression to APAP or TP treatment. Conclusion: Rs2515641 significantly changes CYP2E1 expression and function, which would be expected to affect drug disposition and response.
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Li, Yu-Fen, Fung-Chang Sung, Ming-Hsui Tsai, Chun-Hung Hua, Chiu-Shong Liu, Yao-Te Huang, and Chih-Ching Yeh. "Interactions between Cigarette Smoking and Polymorphisms of Xenobiotic-Metabolizing Genes: The Risk of Oral Leukoplakia." Disease Markers 34, no. 4 (2013): 247–55. http://dx.doi.org/10.1155/2013/983568.
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Background: This case-control study investigates the role of xenobiotic-metabolizing genes, including glutathione S-transferases (GSTs) and cytochrome P450 1A1 (CYP1A1) and 2E1 (CYP2E1), in the susceptibility to oral potentially malignant disorders (OPMDs).Methods: The genotypes of GSTM1, GSTT1, GSTP1, CYP1A1∗2C, and CYP2E1 PstI/RsaI polymorphisms were determined for 217 OPMD cases and 492 age- and sex-matched controls from a Taiwanese penitentiary.Results: Compared to the GSTM1-present genotype, the GSTM1-null genotype was significantly associated with increased risk of leukoplakia (odds ratio [OR]=1.46, 95% l [CI]=1.01–2.10). Similarly, compared to the CYP1A1∗2C A/G+G/G genotype, the CYP1A1∗2C A/A genotype was significantly associated with increased risk of leukoplakia (OR=1.64, 95% CI=1.12–2.40), particularly for smokers consuming > 13 pack-years of cigarettes (OR=2.40, 95% CI=1.40–4.11) (Interaction P=0.039). In addition, participants with 4–5 risk genotypes (OR > 1) experienced higher risks for leukoplakia than those with 0-1 risk genotypes (OR=3.19, 95% CI=1.65–6.15) (Trend test P=0.001).Conclusions: Our findings suggest that the CYP1A1∗2C A/A genotype may increase the risk of leukoplakia, especially for heavy smokers. Xenobiotic-metabolizing genes may simultaneously modulate this disease risk. These observations require further confirmation with larger samples.
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Marsa, Mardhatillah, Yudha Nurhantari, Suhartini Suhartini, and Tri Ratnaningsih. "The Correlation of Cyp2e1 Genetic Polymorphism on Alcohol Drinking Habits in Papuan Ethnicity." Mutiara Medika: Jurnal Kedokteran dan Kesehatan 21, no. 2 (July 29, 2021): 117–23. http://dx.doi.org/10.18196/mmjkk.v21i2.11579.
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Alcohol abuse is associated with genetic factors and is influenced by certain races and ethnicities. CYP2E1, which works on the endoplasmic reticulum, produces an enzyme that plays a significant role in alcohol metabolism. In relation to it, this study aims to identify the polymorphisms of CYP2E1*5B and CYP2E1*6 genes in alcohol drinkers of Papuan Ethnics. A total of 39 Papuans were analyzed for alcohol drinking habits. Alcohol drinkers were found to be 29 people (74.4%), and 10 people (25.6%) were non-drinkers. The drinkers mainly were late teenagers (89,7%) and males (69,2%). The CYP2E1*5B genotypes were c1/c1 as 94.9% and c1/c2 as 5.1%. Meanwhile, the CYP2E1*6 T/T genotypes were 56.4%, and T/A genotypes were 43.6%. The odd ratio for CYP2E1*5B were 18,5 and 7,7 for CYP2E1*6. p0,05 for CYP2E1*5B and CYP2E1*6 gene polymorphisms for alcohol drinking behavior in the form of frequency, duration, type, and volume of alcohol consumed. Furthermore, c1/c1 and c1/c2 genotype polymorphisms were in CYP2E1*5B; T/T and T/A genotypes were in CYP2E1*6 of Papuan ethnic at Yogyakarta. In conclusion, genotype c1/c1 had 18,5 times of the possibility of being alcoholic drinkers, and genotype T/T had 7,7 times of the possibility of being alcoholic drinkers in Papuan ethnic. It indicated that the type of genotype statistically did not significantly affect alcohol drinking behavior on the subject.
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Norton, I. D., M. V. Apte, P. S. Haber, G. W. McCaughan, R. C. Pirola, and J. S. Wilson. "Cytochrome P4502E1 is present in rat pancreas and is induced by chronic ethanol administration." Gut 42, no. 3 (March 1, 1998): 426–30. http://dx.doi.org/10.1136/gut.42.3.426.
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Background—The mechanisms responsible for the initiation of alcoholic pancreatitis remain elusive. However, there is an increasing body of evidence that reactive oxygen species play a role in both acute and chronic pancreatitis. In the liver, cytochrome P4502E1 (CYP2E1, the inducible ethanol metabolising enzyme) is one of the proposed pathways by which ethanol induces oxidative stress.Aims—To determine whether CYP2E1 is present in the pancreas and, if so, whether it is inducible by chronic ethanol feeding.Methods—Eighteen male Sprague-Dawley rats were pair fed liquid diets with or without ethanol as 36% of energy for four weeks. CYP2E1 levels were determined by western blotting of microsomal protein from both pancreas and liver. Messenger RNA (mRNA) levels for CYP2E1 were quantified using dot blots of total pancreatic RNA.Results—CYP2E1 was found in the pancreas. Furthermore, the amount of CYP2E1 was greater in the pancreas of rats fed ethanol compared with controls (mean increase over controls 5.1-fold, 95% confidence intervals 2.4 to 7.7, p<0.02). In the liver, induction by ethanol of CYP2E1 was similar (mean increase over controls 7.9-fold, 95% confidence intervals 5.2 to 10.6, p<0.005). Pancreatic mRNA levels for CYP2E1 were similar in ethanol fed and control rats.Conclusions—CYP2E1 is present in the rat pancreas and is inducible by chronic ethanol administration. Induction of pancreatic CYP2E1 is not regulated at the mRNA level. The metabolism of ethanol via CYP2E1 may contribute to oxidative stress in the pancreas during chronic ethanol consumption.
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Konstandi, Maria, Jie Cheng, and Frank J. Gonzalez. "Sex steroid hormones regulate constitutive expression of Cyp2e1 in female mouse liver." American Journal of Physiology-Endocrinology and Metabolism 304, no. 10 (May 15, 2013): E1118—E1128. http://dx.doi.org/10.1152/ajpendo.00585.2012.
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CYP2E1 is of paramount toxicological significance because it metabolically activates a large number of low-molecular-weight toxicants and carcinogens. In this context, factors that interfere with Cyp2e1 regulation may critically affect xenobiotic toxicity and carcinogenicity. The aim of this study was to investigate the role of female steroid hormones in the regulation of CYP2E1, as estrogens and progesterone are the bases of contraceptives and hormonal replacement therapy in menopausal women. Interestingly, a fluctuation in the hepatic expression pattern of Cyp2e1 was revealed in the different phases of the estrous cycle of female mice, with higher Cyp2e1 expression at estrus (E) and lower at methestrus (ME), highly correlated with that in plasma gonadal hormone levels. Depletion of sex steroids by ovariectomy repressed Cyp2e1 expression to levels similar to those detected in males and cyclic females at ME. Hormonal supplementation brought Cyp2e1 expression back to levels detected at E. The role of progesterone appeared to be more prominent than that of 17β-estradiol. Progesterone-induced Cyp2e1 upregulation could be attributed to inactivation of the insulin/PI3K/Akt/FOXO1 signaling pathway. Tamoxifen, an anti-estrogen, repressed Cyp2e1 expression potentially via activation of the PI3K/Akt/FOXO1 and GH/STAT5b-linked pathways. The sex steroid hormone-related changes in hepatic Cyp2e1 expression were highly correlated with those observed in Hnf-1α, β-catenin, and Srebp-1c. In conclusion, female steroid hormones are clearly involved in the regulation of CYP2E1, thus affecting the metabolism of a plethora of toxicants and carcinogenic agents, conditions that may trigger several pathologies or exacerbate the outcomes of various pathophysiological states.
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Yu, Jin, Hong Zhu, Mark S. Kindy, and Saeid Taheri. "Cytochrome P450 CYP2E1 Suppression Ameliorates Cerebral Ischemia Reperfusion Injury." Antioxidants 10, no. 1 (January 5, 2021): 52. http://dx.doi.org/10.3390/antiox10010052.
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Despite existing strong evidence on oxidative markers overproduction following ischemia/reperfusion (I/R), the mechanism by which oxidative enzyme Cytochrome P450-2E1 (CYP2E1) contributes to I/R outcomes is not clear. In this study, we sought to evaluate the functional significance of CYP2E1 in I/R. CYP2E1 KO mice and controls were subjected to middle cerebral artery occlusion (MCAo-90 min) followed by 24 h of reperfusion to induce focal I/R injury as an acute stage model. Then, histological and chemical analyses were conducted to investigate the role of CYP2E1 in lesion volume, oxidative stress, and inflammation exacerbation. Furthermore, the role of CYP2E1 on the blood-brain barrier (BBB) integrity was investigated by measuring 20-hydroxyecosatetraenoic acid (20-HETE) activity, as well as, in vivo BBB transfer rate. Following I/R, the CYP2E1 KO mice exhibited a significantly lower lesion volume, and neurological deficits compared to controls (p < 0.005). Moreover, reactive oxygen species (ROS) production, apoptosis, and neurodegeneration were significantly lower in the CYP2E1(−/−) I/R group (p < 0.001). The BBB damage was significantly lower in CYP2E1(−/−) mice compared to wild-type (WT) (p < 0.001), while 20-HETE production was increased by 41%. Besides, inflammatory cytokines expression and the number of activated microglia were significantly lower in CYP2E1(−/−) mice following I/R. CYP2E1 suppression ameliorates I/R injury and protects BBB integrity by reducing both oxidative stress and inflammation.
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Forsyth, Christopher B., Robin M. Voigt, Maliha Shaikh, Yueming Tang, Arthur I. Cederbaum, Fred W. Turek, and Ali Keshavarzian. "Role for intestinal CYP2E1 in alcohol-induced circadian gene-mediated intestinal hyperpermeability." American Journal of Physiology-Gastrointestinal and Liver Physiology 305, no. 2 (July 15, 2013): G185—G195. http://dx.doi.org/10.1152/ajpgi.00354.2012.
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We have shown that alcohol increases Caco-2 intestinal epithelial cell monolayer permeability in vitro by inducing the expression of redox-sensitive circadian clock proteins CLOCK and PER2 and that these proteins are necessary for alcohol-induced hyperpermeability. We hypothesized that alcohol metabolism by intestinal Cytochrome P450 isoform 2E1 (CYP2E1) could alter circadian gene expression ( Clock and Per2), resulting in alcohol-induced hyperpermeability. In vitro Caco-2 intestinal epithelial cells were exposed to alcohol, and CYP2E1 protein, activity, and mRNA were measured. CYP2E1 expression was knocked down via siRNA and alcohol-induced hyperpermeability, and CLOCK and PER2 protein expression were measured. Caco-2 cells were also treated with alcohol or H2O2 with or without N-acetylcysteine (NAC) anti-oxidant, and CLOCK and PER2 proteins were measured at 4 or 2 h. In vivo Cyp2e1 protein and mRNA were also measured in colon tissue from alcohol-fed mice. Alcohol increased CYP2E1 protein by 93% and enzyme activity by 69% in intestinal cells in vitro. Alcohol feeding also increased mouse colonic Cyp2e1 protein by 73%. mRNA levels of Cyp2e1 were not changed by alcohol in vitro or in mouse intestine. siRNA knockdown of CYP2E1 in Caco-2 cells prevented alcohol-induced hyperpermeability and induction of CLOCK and PER2 proteins. Alcohol-induced and H2O2-induced increases in intestinal cell CLOCK and PER2 were significantly inhibited by treatment with NAC. We concluded that our data support a novel role for intestinal CYP2E1 in alcohol-induced intestinal hyperpermeability via a mechanism involving CYP2E1-dependent induction of oxidative stress and upregulation of circadian clock proteins CLOCK and PER2.
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Cao, Qi, Ki M. Mak, and Charles S. Lieber. "Cytochrome P4502E1 primes macrophages to increase TNF-α production in response to lipopolysaccharide." American Journal of Physiology-Gastrointestinal and Liver Physiology 289, no. 1 (July 2005): G95—G107. http://dx.doi.org/10.1152/ajpgi.00383.2004.
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Kupffer cells become activated in response to elevated levels of LPS during ethanol feeding, but the role of ethanol in the molecular processes of activation remains unclear. Because cytochrome P4502E1 (CYP2E1) is upregulated in Kupffer cells after ethanol, we hypothesized that this effect primes Kupffer cells, sensitizing them to increase TNF-α production in response to LPS. However, cultured Kupffer cells rapidly lose their CYP2E1. This difficulty was overcome by transfecting CYP2E1 to RAW 264.7 macrophages. Macrophages with stable increased CYP2E1 expression (E2) displayed increased levels of CD14/Toll-like receptor 4, NADPH oxidase and H2O2, accompanied by activation of ERK1/2, p38, and NF-κB. These increases primed E2 cells, sensitizing them to LPS stimuli, with amplification of LPS signaling, resulting in increased TNF-α production. Diphenyleneiodonium, a NADPH oxidase inhibitor, and diallyl sulfide, a CYP2E1 inhibitor, decreased approximately equally H2O2levels in E2 cells, suggesting that NADPH oxidase and CYP2E1 contribute equally to H2O2generation. Because CYP2E1 expression also enhanced the levels of the membrane localized NADPH oxidase subunits p47phoxand p67phox, thereby contributing to the oxidase activation, it may augment H2O2generation via this mechanism. H2O2, derived in part from NADPH and CYP2E1, activated ERK1/2 and p38. ERK1/2 stimulated TNF-α production via activation of NF-κB, whereas p38 promoted TNF-α production by stabilizing TNF-α mRNA. Oxidant generation after CYP2E1 overexpression appears to be central to macrophage priming and their sensitization to LPS. Accordingly, CYP2E1 priming could explain the sensitization of Kupffer cells to LPS activation by ethanol, a critical early step in alcoholic liver disease.
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Samgina, T. A., P. M. Nazarenko, A. V. Polonikov, and V. A. Lazarenko. "The role of some xenobiotic biotransformation genes snp in the development of acute pancreatitis." Bulletin of Russian State Medical University, no. (1)2020 (February 15, 2020): 34–39. http://dx.doi.org/10.24075/brsmu.2020.008.
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Genetically determined features of the xenobiotic biotransformation system play an important role in the development of acute pancreatitis (AP) and its complications. The aim of this study was to assess the contribution of 3 SNPs (CYP1A1 -462 T>C rs1048943, CYP2E1 -1293 G>C rs3813867 and ABCB1 -3435 G>A rs1045642) to the development of AP and its complications. DNA samples were collected from 547 unrelated patients with AP (154 women and 393 men; mean age 48.9 ± 13.1 years) undergoing therapy at surgery departments of Kursk and 573 unrelated individuals without gastrointestinal diseases (161 women and 412 men; mean age 47.8 ± 12.1 years). The polymorphisms were genotyped by PCR using TaqMan probes for allele discrimination. Infected pancreatic necrosis (IPN) was observed in 97 patients; 101 patients developed a pseudocyst (PC); 111 patients had a peripancreatic necrosis (PN). AP was the most common in the carriers of the А allele in ABCB1 G>A (rs1045642) (p = 0.0008). The carriers of the G/G genotype rarely developed both AP (p = 5·10–4) and its complications: IPN (p = 0.03R), PN (p = 0.036R), PC (p = 0.04R). The carriers of the G/C–C/C CYP2E1 G>C (rs3813867) genotypes who had no long-term history of alcohol abuse rarely developed AP (p = 0.03). The carriers of the G/C CYP2E1 (rs3813867) genotype tended to develop pseudocysts (p = 0.05OD). AP was more frequently complicated by IPN (p = 0.009R), PN (p = 0.003R) and PC (p = 0.003D) in the carriers of the C/C CYP1A1 T>C (rs1048943) genotype. A milder course of AP was typical for the carriers of the G/G ABCB1 G>A (rs1045642) genotype; a more severe course was characteristic of the carriers of the C/C CYP1A1 T>C (rs1048943) genotype.
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Sepuri, Naresh B. V., Sanjay Yadav, Hindupur K. Anandatheerthavarada, and Narayan G. Avadhani. "Mitochondrial targeting of intact CYP2B1 and CYP2E1 and N-terminal truncated CYP1A1 proteins in Saccharomyces cerevisiae − role of protein kinase A in the mitochondrial targeting of CYP2E1." FEBS Journal 274, no. 17 (August 14, 2007): 4615–30. http://dx.doi.org/10.1111/j.1742-4658.2007.05990.x.
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Bernauer, Ulrike, Hansruedi Glatt, Barbara Heinrich-Hirsch, Yungang Liu, Eva Muckel, Bärbel Vieth, and Ursula Gundert-Remy. "Heterologous Expression of Mouse Cytochrome P450 2e1 in V79 Cells: Construction and Characterisation of the Cell Line and Comparison with V79 Cell Lines Stably Expressing Rat P450 2E1 and Human P450 2E1." Alternatives to Laboratory Animals 31, no. 1 (January 2003): 21–30. http://dx.doi.org/10.1177/026119290303100104.
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A V79 Chinese hamster cell line was constructed for stable expression of mouse cytochrome P450 2e1 (Cyp2e1), as an addition to the existing cell battery consisting of cell lines stably expressing rat CYP2E1 and human CYP2E1 (V79 Cell Battery™). The aim was to establish a cell battery that offers the in vitro possibility of investigating species-specific differences in the toxicity and metabolism of chemicals representing substrates for CYP2E1. The newly established cell line (V79m2E1) effectively expressed Cyp2e1 in the catalytically active form. The expression of catalytically active CYP2E1 in V79m2E1 cells was maintained over several months in culture, as demonstrated by Western Blotting and chlorzoxazone (CLX) 6-hydroxylase activity. The cells exhibited CLX 6-hydroxylase activity with a Km of 27.8μM/l and Vmax of 40pmol/mg protein/minute, compared with a Km of 28.2/28.6μM/l and a Vmax of 130/60pmol/mg protein/minute from V79r2E1/V79h2E1 cells. Furthermore, the CYP2E1-dependent mutagenicity of N-nitrosodimethylamine could be demonstrated in the V79m2E1 cells. Therefore, the new cell battery permits the interspecies comparison of CYP2E1-dependent toxicity and of metabolism of chemicals between humans and the two major rodent species — the rat and the mouse — that are usually used in classical toxicity studies.
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Seitz, Helmut, and Sebastian Mueller. "Die Bedeutung von Cytochrom P4502E1 bei der alkoholischen Lebererkrankung und bei der alkoholmediierten Karzinogenese." Zeitschrift für Gastroenterologie 57, no. 01 (January 2019): 37–45. http://dx.doi.org/10.1055/a-0784-8815.
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ZusammenfassungVerschiedene Faktoren sind in der Pathogenese der alkoholischen Lebererkrankung (ALE) und der alkoholvermittelten Karzinogenese beteiligt. Neben genetischen, epigenetischen und immunologischen Mechanismen spielen die toxische Wirkung von Acetaldehyd, oxidativer Stress und zytokinvermittelte Entzündungen eine wesentliche Rolle. Oxidativer Stress mit der Generierung von reaktiven Sauerstoffspezies (ROS) entsteht entweder in der Entzündung (alkoholische Hepatitis) oder bei der Alkoholoxidation via Cytochrom P4502E1 (CYP2E1). CYP2E1 wird durch Alkohol induziert, oxidiert Äthanol zu Acetaldehyd und generiert dabei ROS. ROS führt unter anderem zu Proteinschädigung, Fibrogenese und DNA-Mutationen. Weiterhin resultiert die CYP2E1-Induktion in einer gesteigerten Prokarzinogenaktivierung und einem verstärkten Abbau von Retinol und Retinsäure, einem Faktor, der für eine geordnete Zelldifferenzierung und Zellproliferation verantwortlich ist. Eine Hemmung von CYP2E1 führt zu einer Verbesserung der ALE und zu einer Hemmung der chemisch induzierten Karzinogenese im Tierexperiment. Beim Menschen wird CYP2E1 bereits bei 40 Gramm Alkohol pro Tag innerhalb einer Woche induziert, jedoch gibt es signifikante interindividuelle Unterschiede. Der Mechanismus dafür ist unklar. Bei Patienten mit ALE korreliert CYP2E1 mit dem Ausmaß von hochkarzinogenen Etheno-DNA-Addukten in Leber und Ösophagus und mit der Schwere der Leberfibrose. Erste Ergebnisse zu einer Hemmung von CYP2E1 durch Chlormethiazol, einem spezifischen CYP2E1-Hemmer, bei Patienten mit ALE sind in Kürze zu erwarten.
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García-Suástegui, W. A., L. A. Ramos-Chávez, M. Rubio-Osornio, M. Calvillo-Velasco, J. A. Atzin-Méndez, J. Guevara, and D. Silva-Adaya. "The Role of CYP2E1 in the Drug Metabolism or Bioactivation in the Brain." Oxidative Medicine and Cellular Longevity 2017 (2017): 1–14. http://dx.doi.org/10.1155/2017/4680732.
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Organisms have metabolic pathways that are responsible for removing toxic agents. We always associate the liver as the major organ responsible for detoxification of the body; however this process occurs in many tissues. In the same way, as in the liver, the brain expresses metabolic pathways associated with the elimination of xenobiotics. Besides the detoxifying role of CYP2E1 for compounds such as electrophilic agents, reactive oxygen species, free radical products, and the bioactivation of xenobiotics, CYP2E1 is also related in several diseases and pathophysiological conditions. In this review, we describe the presence of phase I monooxygenase CYP2E1 in regions of the brain. We also explore the conditions where protein, mRNA, and the activity of CYP2E1 are induced. Finally, we describe the relation of CYP2E1 in brain disorders, including the behavioral relations for alcohol consumption via CYP2E1 metabolism.
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Shankar, Kartik, Xiaoli Liu, Rohit Singhal, Jin-Ran Chen, Shanmugam Nagarajan, Thomas M. Badger, and Martin J. J. Ronis. "Chronic Ethanol Consumption Leads to Disruption of Vitamin D3 Homeostasis Associated with Induction of Renal 1,25 Dihydroxyvitamin D3-24-Hydroxylase (CYP24A1)." Endocrinology 149, no. 4 (December 27, 2007): 1748–56. http://dx.doi.org/10.1210/en.2007-0903.
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Bone loss resulting from chronic ethanol (EtOH) abuse is frequently accompanied by altered vitamin D3 homeostasis. In the current study, we examined EtOH effects in a female rat model in which control or EtOH-containing diets were infused intragastrically. EtOH treatment reduced plasma 1,25-dihydroxycholecalciferol (1,25 (OH)2 D3) coincident with a decrease in renal CYP27B1 (25(OH)D3 1α-hydroxylase) mRNA and an increase in expression of renal CYP24A1 (1,25 (OH)2 D3- 24-hydroxylase). EtOH induction of CYP24A1 occurred as a result of increased transcription and was also observed in vitro in primary cultures of rat renal proximal tubule cells (RPTCs) and in NRK-52E cells. Synergistic induction of CYP24A1 by EtOH in combination with 1,25 (OH)2 D3 was observed. The major EtOH metabolizing enzymes, alcohol dehydrogenase-1 and CYP2E1, were induced by EtOH in RPTCs. Inhibition of EtOH metabolism by 4-methylpyrazole inhibited the induction of CYP24A1 mRNA. CYP24A1 mRNA induction in RPTCs was also inhibited by the protein synthesis inhibitor cycloheximide. CYP24A1 was also induced after hydrogen peroxide treatment, and EtOH treatment of RPTCs resulted in production of reactive oxygen species as measured by flow cytometry using the fluorescent probe dichlorofluorescin acetate. In addition, inhibition of MAPK signaling pathways with the MAPK kinase inhibitor U0126 or the p38 inhibitor SB203580 inhibited EtOH induction of CYP24A1. Our data suggest that EtOH reduces circulating 1,25 (OH)2 D3 concentrations as the result of CYP24A1 induction that is mediated via MAPK activation resulting from renal oxidative stress produced by local metabolism of EtOH via CYP2E1 and antidiuretic hormone-1.
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Hoffler, Undi, and Burhan I. Ghanayem. "INCREASED BIOACCUMULATION OF URETHANE IN CYP2E1-/- VERSUS CYP2E1+/+ MICE." Drug Metabolism and Disposition 33, no. 8 (May 6, 2005): 1144–50. http://dx.doi.org/10.1124/dmd.105.003806.
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Neafsey, Pat, Gary Ginsberg, Dale Hattis, Douglas O. Johns, Kathryn Z. Guyton, and Babasaheb Sonawane. "Genetic Polymorphism in CYP2E1: Population Distribution of CYP2E1 Activity." Journal of Toxicology and Environmental Health, Part B 12, no. 5-6 (October 8, 2009): 362–88. http://dx.doi.org/10.1080/10937400903158359.
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Seth, Ratanesh K., Varun Chandrashekaran, Diptadip Dattaroy, Firas Alhasson, Mitzi Nagarkatti, Prakash Nagarkatti, Anna Mae Diehl, Wolfgang Liedtke, and Saurabh Chatterjee. "TRPV4 attenuates M1 polarization and subsequent NASH progression by stalling CYP2E1-mediated redox toxicity via eNOS." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 197.13. http://dx.doi.org/10.4049/jimmunol.198.supp.197.13.
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Abstract M1 macrophage polarization in nonalcoholic steatohepatitis (NASH) liver has been impacted by several exogenous or endogenous factors including inflammatory stimuli, oxidative stress, and cytokines. In absence of an active endogenous defense mechanism, the M1 polarization bias potentiates NASH progression by intensified inflammation and intermittent fibrosis in the rodent model of liver injury. We introduce an endogenous defense mechanism in the liver that is mediated by TRPV4, a transient receptor potential calcium-permeable ion channel that responds to the cytotoxic liver environment and negatively regulates CYP2E1. We hypothesized that CYP2E1-mediated oxidative stress causes M1 polarization in experimental NASH and active TRPV4 inhibits CYP2E1 mediated inflammation with concomitant attenuation of M1 polarization. Since CYP2E1 takes center stage in redox toxicity we use a toxin model of NASH which uses pyrazole, a ligand and a substrate of CYP2E1 for inducing liver injury with NASH-like phenotype. Using both cyp2e1−/− and trpv4−/− mice, we show that in the absence of active TRPV4, CYP2E1 induced oxidative stress causes M1 polarization bias, that includes a significant increase in IL-1β, IL-12, IL-6 and IL-23 while CYP2E1 null or diallyl sulfide treated mice prevent it. Recently, we discovered that the TRPV4 modulates eNOS activation and nitric oxide release from Kupffer cell during an early stage of liver injury. Based on the adaptive NO increase in trpv4+/+ mice, NO donor administration in trpv4−/− mice abrogated CYP2E1-induced oxidative stress, M1 polarization, and NASH progression. Thus, a novel endogenous defense molecule TRPV4 can be a promising immunotherapeutic approach against chronic liver injury.
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Massart, Julie, Karima Begriche, Jessica H. Hartman, and Bernard Fromenty. "Role of Mitochondrial Cytochrome P450 2E1 in Healthy and Diseased Liver." Cells 11, no. 2 (January 15, 2022): 288. http://dx.doi.org/10.3390/cells11020288.
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Cytochrome P450 2E1 (CYP2E1) is pivotal in hepatotoxicity induced by alcohol abuse and different xenobiotics. In this setting, CYP2E1 generates reactive metabolites inducing oxidative stress, mitochondrial dysfunction and cell death. In addition, this enzyme appears to play a role in the progression of obesity-related fatty liver to nonalcoholic steatohepatitis. Indeed, increased CYP2E1 activity in nonalcoholic fatty liver disease (NAFLD) is deemed to induce reactive oxygen species overproduction, which in turn triggers oxidative stress, necroinflammation and fibrosis. In 1997, Avadhani’s group reported for the first time the presence of CYP2E1 in rat liver mitochondria, and subsequent investigations by other groups confirmed that mitochondrial CYP2E1 (mtCYP2E1) could be found in different experimental models. In this review, we first recall the main features of CYP2E1 including its role in the biotransformation of endogenous and exogenous molecules, the regulation of its expression and activity and its involvement in different liver diseases. Then, we present the current knowledge on the physiological role of mtCYP2E1, its contribution to xenobiotic biotransformation as well as the mechanism and regulation of CYP2E1 targeting to mitochondria. Finally, we discuss experimental investigations suggesting that mtCYP2E1 could have a role in alcohol-associated liver disease, xenobiotic-induced hepatotoxicity and NAFLD.
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Liu, Hailing, Brett E. Jones, Cynthia Bradham, and Mark J. Czaja. "Increased cytochrome P-450 2E1 expression sensitizes hepatocytes to c-Jun-mediated cell death from TNF-α." American Journal of Physiology-Gastrointestinal and Liver Physiology 282, no. 2 (February 1, 2002): G257—G266. http://dx.doi.org/10.1152/ajpgi.00304.2001.
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The mechanisms underlying hepatocyte sensitization to tumor necrosis factor-α (TNF-α)-mediated cell death remain unclear. Increases in hepatocellular oxidant stress such as those that occur with hepatic overexpression of cytochrome P-450 2E1 (CYP2E1) may promote TNF-α death. TNF-α treatment of hepatocyte cell lines with differential CYP2E1 expression demonstrated that overexpression of CYP2E1 converted the hepatocyte TNF-α response from proliferation to apoptotic and necrotic cell death. Death occurred despite the presence of increased levels of nuclear factor-κB transcriptional activity and was associated with increased lipid peroxidation and GSH depletion. CYP2E1-overexpressing hepatocytes had increased basal and TNF-α-induced levels of c-Jun NH2-terminal kinase (JNK) activity, as well as prolonged JNK activation after TNF-α stimulation. Sensitization to TNF-α-induced cell death by CYP2E1 overexpression was inhibited by antioxidants or adenoviral expression of a dominant-negative c-Jun. Increased CYP2E1 expression sensitized hepatocytes to TNF-α toxicity mediated by c-Jun and overwhelming oxidative stress. The chronic increase in intracellular oxidant stress created by CYP2E1 overexpression may serve as a mechanism by which hepatocytes are sensitized to TNF-α toxicity in liver disease.
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Santoso, Setiyo Budi, Puji Umi Chabibah, and Prasojo Pribadi. "Resiko Hepatotoksik Populasi Indonesia Akibat Polimorfisme Enzim NAT2 dan CYP2E1 dalam Metabolisme Isoniazid." Urecol Journal. Part D: Applied Sciences 1, no. 1 (April 20, 2021): 9–16. http://dx.doi.org/10.53017/ujas.11.
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Artikel ini menyajikan data profil resiko kejadian hepatotoksik akibat polimorfisme NAT2 dan CYP2E1 dalam metabolisme isoniazid pada populasi Indonesia di antara berbagai populasi sejumlah negara. Penelitian berlangsung melalui telaah pustaka yang diperoleh dari google schoolar. Pencarian pustaka menggunakan tiga varian kata kunci; (1) “pharmacogenomic dan tuberculosis dan INH dan NAT2 dan CYP2E1 dan polymorphism”, (2) “isoniazid dan hepatotoxicity dan polymorphism dan N-acetyltransferase”, (3) “isoniazid dan hepatotoxicity dan polymorphism dan CYP2E1”. Analisis resiko hepatotoksik berdasarkan nilai odd ratio (confidence interval) menggunakan software Stata MP edisi 14. Telaah resiko hepatotoksik berdasarkan ragam kecepatan asetilasi NAT2 melibatkan 2.140 populasi dari 8 negara, sedangkan telaah resiko berdasarkan ragam alel CYP2E1 melibatkan 1.530 populasi dari 5 negara. Hasil telaah pustaka menunjukkan bahwa resiko hepatotoksik akibat induksi isoniazid pada populasi Indonesia yang memiliki enzim NAT2 asetilator lambat dan orang dengan CYP2E1*c1/c2, tiga kali lebih tinggi dari populasi lain di berbagai negara. Potensi resiko akan meningkat pada orang yang memiliki kombinasi NAT2 asetilator lambat dan CYP2E1*c1/c2.
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Li, Fang, Rongzhu Lu, Ting Zhao, Xinyu Zhang, Suhua Wang, and Guangwei Xing. "Comparing the protective effects of three sulfur compounds against acrylonitrile-induced acute toxicity in CYP2E1-induced rats." Toxicology and Industrial Health 35, no. 5 (April 16, 2019): 387–97. http://dx.doi.org/10.1177/0748233719839847.
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Cytochrome P450 2E1 (CYP2E1) can be induced by diabetes mellitus, nonalcoholic liver disease, and obesity. This study assessed the protective effects of three sulfur compounds, namely phenethyl isothiocyanate (PEITC), dimethyl trisulfide (DMTS), and sodium thiosulfate (STS), on acrylonitrile (ACN)-induced acute toxicity in rats enriched with CYP2E1. PEITC and DMTS were administered intragastrically (i.g.), whereas STS was injected intraperitoneally (i.p.) at an identical dose of 0.5 mmol/kg for 3 days in acetone-pretreated rats before ACN (90 mg/kg) injection (i.p.). Acetone-treated rats that expressed high levels of CYP2E1 were more susceptible to ACN-induced acute toxicity. The sulfur compounds reduced the rate of convulsions and loss of the righting reflex in acute ACN-exposed CYP2E1-induced rats; PEITC and DMTS also increased the survival rates. PEITC inhibited hepatic CYP2E1 activity and protected hepatic and cerebral cytochrome c oxidase (CcOx) activities in acute ACN-exposed CYP2E1-enriched rats; DMTS protected hepatic CcOx activity. DMTS attenuated ACN-induced oxidative injury by reducing malondialdehyde (MDA) levels and increasing glutathione content in the brain. STS only reduced cerebral MDA levels, whereas PEITC did not exhibit any antioxidant effects. Collectively, PEITC provided superior protective effects against ACN-induced acute toxicity in rats with increased CYP2E1 activity, followed by DMTS; STS provided limited effects. PEITC and DMTS might be considered as promising chemopreventive agents against ACN-induced acute toxicity in vulnerable subpopulations with increased CYP2E1 activity.
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Farhat, Farhat, Elvita Rahmi Daulay, Jessy Chrestella, and Raudah Putri Syari. "The Association of CYP2E1 Polymorphism and Environmental Factor in Nasopharyngeal Carcinoma Patients." Open Access Macedonian Journal of Medical Sciences 8, B (March 25, 2020): 362–67. http://dx.doi.org/10.3889/oamjms.2020.4639.
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INTRODUCTION: Polymorphism of CYP2E1 induces nasopharyngeal carcinoma (NPC) by activating pro-carcinogens including nitrosamine. Environmental factor such as salted fish, preserved food, tobacco, and alcohol consumption which contains nitrosamine, join with CYP2E1 polymorphism leads to an increase of susceptibility for NPC.
OBJECTIVE: The aims of this study were to identify CYP2E1 polymorphism and the association with other risk factors to NPC in NPC patients.
METHODS: This study was analytic research with the case–control design. The samples were taken based on non-probability consecutive sampling method. The identification of CYP2E1 polymorphism was done by the PCR-RFLP method. The association of its variable to NPC was analyzed with the Chi-square test and between polymorphism of CYP2E1 with other risk factors was analyzed with stratified analysis.
RESULT: We found that there was no significant association of CYP2E1 polymorphism with NPC. However, the joint effect of CYP2E1 polymorphism with smoking was significant in NPC patients. The risk for NPC in the combination of those two was 4.0-fold.
CONCLUSION: The study showed the capability of genetics and environment in the development of NPC. Further study can be done to find evidence of genetics and environmental influence in the prevention and treatment of NPC.
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Peng, Zhicheng, Xiaobing Li, Zhe Wang, Guowen Liu, and Xinwei Li. "The effects of non-esterified fatty acids and β-hydroxybutyrate on the hepatic CYP2E1 in cows with clinical ketosis." Journal of Dairy Research 86, no. 1 (February 2019): 68–72. http://dx.doi.org/10.1017/s0022029919000025.
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AbstractDairy cows with ketosis display severe oxidative stress as well as high blood concentrations of non-esterified fatty acids (NEFA) and β-hydroxybutyrate (BHB). Cytochrome P4502E1 (CYP2E1) plays an important role in the induction of oxidative stress. The aim of this study was to investigate CYP2E1 expression and activity in the liver of clinically ketotic cows (in vivo) and the effects of NEFA and BHB on CYP2E1 expression and activity in hepatocytes (in vitro). Dairy cows with clinical ketosis exhibited a low blood concentration of glucose but high concentrations of NEFA and BHB. Hepatic mRNA, protein expression, and activity of CYP2E1 were significantly higher in cows with clinical ketosis than in control cows. In vitro, both NEFA and BHB treatment markedly up-regulated the mRNA and protein expressions as well as activity of CYP2E1 in cow hepatocytes. Taken together, these results indicate that high levels of NEFA and BHB significantly up-regulate the expression and activity of hepatic CYP2E1, and may be influential in the induction of oxidative stress in cows with clinical ketosis.
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Wang, Jishi, Xiaoyan Hu, Xinmei Liu, Yuan Yang, Yingya Wu, and Qin Fang. "The Anticancer Effect of Cytochrome P450 2E1 Gene Which Was Mediated by Recombination Adenovirus in Mesenchymal Stem Cells." Blood 108, no. 11 (November 16, 2006): 4737. http://dx.doi.org/10.1182/blood.v108.11.4737.4737.
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Abstract Dacarbazine (DTIC) can inhibit purine nucleotide synthesis after activated by P4502E1(CYP2E1) in liver and can be used for the treatment of malignant melanoma and Hodgkins lymphoma. Objective: To explore the anticancer effect of the combination of CYP2E1 and DTIC. Methods: A full length cDNA fragment encoding the human CYP2E1 was cloned and was transfected into bone marrow mesenchymal stem cells (BMSCs) through recombinant adenovirus vector. The recombinant adenovirus vectors pAd5CMV-CYP2E1 and pAd5CMV-EGFP were constructed and transfected into the packing cell lines HEK293 cells by liposome encapsulation method. The expression of CYP2E1 gene was detected by Real-time PCR and Western Blot and contrasted to the cells which were transfected into the recombinant adenovirus including EGFP. In vitro, gene transfected BMSCs were co-cultured with DTIC, and then the supernatant was added into the medium of human malignant melanoma M14 cells. Fluorescence microscopy, DNA Ladder, flowcytometry, electrophoresis were employed to tests the apoptosis, and MTT method was applied to detecting the IC50. In the animal experiment, the CYP2E1 gene tranfected BMSCs were injected in combination with DTIC directly into the malignant melanomas on nude mice or through caudal vein, and the injected BMSCs transfected pAd5CMV-EGFP and DTIC in the same manner into nude control mice. The inhibiting effect of new planted tumors of experimental group was monitored through Immuno-histochemistry analysis and the shape and size of tumors were measured. CYP2E1-EGFP gene tranfected BMSCs were injected into nude mice through caudal vein and tracked by fluorescence. Results: CYP2E1 gene(1482bp) was cloned successfully and it was conformed by DNA sequencing; Endonuclease and PCR analyses showed that recombinant adenovirus vector had been constructed and high titer recombinant adenovirosome(1×1012pfu/ml) had been packaged successfully. BMSCs had been isolated and flowcytometry showed their phenotype were CD44(+),CD105(+), CD34(−)and CD45(−). The mRNA and protein quantities of the group of CYP2E1 gene tranfected BMSCs were significantly higher than the control group (P<0.05, n=24). In vitro, immunity fluorescence microscope, DNA Ladder, and flowcytometry all showed the supernatant of co-culture of CYP2E1 gene tranfected BMSCs and DTIC) significantly decreased the mortality of M14 cells compared with pAd5CMV-EGFP-BMSCs control group (P < 0. 05, n=24). In vivo, the sizes of the tumor in the nude mice treated with transfected BMSCs and DTIC were significantly smaller than control case and changed along with concentration. (P< 0.05, n=20). No new tumor was found in the nude mouse inoculated with M14 cells after the injection of CYP2E1 transfected BMSCs and DTIC. Conclusion: Recombination adenovirus vector was able to express CYP2E1 in BMSCs. Gene CYP2E1 transfected BMSCs and DTIC showed anticancer activity both in vitro and vivo.
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Iwahashi, K., K. Nakamura, A. Furukawa, E. Okuyama, R. Miyatake, Y. Ichikawa, and H. Suwaki. "No linkage of the cytochrome P-450IIE1 (CYP2E1) C1/C2 polymorphism to schizophrenia." Human & Experimental Toxicology 16, no. 4 (April 1997): 208–11. http://dx.doi.org/10.1177/096032719701600409.
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We investigated, using PCR-SSCP analysis, the relation ship between schizophrenia and the polymorphism of d- benzphetamine N-demethylase (cytochrome P-450j or CYP2E1), which metabolizes psychotropic substances such as d-benzphetamine and alcohols. Among 41 patients with schizophrenia, no statistically significant change in the frequency of the mutant (C2) allele relative to in controls was found, and no novel structural mutation in the CYP2E1 gene, which would be expected to alter the CYP2E1 protein, was found. This could be explained by no linkage of the CYP2E1 gene (mutations in the exon 1- 9, and C1/C2 polymorphism) to schizophrenia.
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Kwon, Mi Hye, Cheol Jung Lee, Yong Yeon Cho, and Hee Eun Kang. "Pharmacokinetics of a Cytochrome P450 2E1 Probe, Chlorzoxazone, and its 6-Hydroxy Metabolite in Poloxamer 407-Induced Hyperlipidemic Rats." Journal of Pharmacy & Pharmaceutical Sciences 16, no. 4 (November 6, 2013): 648. http://dx.doi.org/10.18433/j3dw3s.
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Purpose. To evaluate the possible changes in CYP2E1 expression and activity in hyperlipidemia (HL), we evaluated the pharmacokinetics of chlorzoxazone (CZX) as a CYP2E1 probe in rats with HL induced by poloxamer 407 (HL rats). Methods. The pharmacokinetics of CZX and its 6-hydroxy metabolite (OH-CZX) were evaluated after intravenous administration of 20 mg/kg CZX to both control and HL rats. We also examined changes in the expression of CYP2E1 and its in vitro metabolic activity in hepatic microsomal fractions from HL rats. Results. The total area under the plasma concentration–time curve (AUC) of CZX in the HL rats after its intravenous administration was comparable with that in the controls due to unchanged non-renal clearance (CLNR). The AUC of OH-CZX and AUCOH-CZX/AUCCZX ratios in HL rats also remained unchanged. This was primarily due to the comparable hepatic CLint for metabolism of CZX to OH-CZX via CYP2E1 between the control and HL rats as a result of unchanged expression of CYP2E1 in HL rats. Conclusions. This is the first study to evaluate CYP2E1 expression and activity in HL rats and their effects on the pharmacokinetics of a CYP2E1 probe drug. These findings have potential therapeutic implications assuming that the HL rat model qualitatively reflects similar changes in patients with HL.
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Collom, Samuel L., Ryan M. Laddusaw, Amber M. Burch, Petr Kuzmic, Martin D. Perry, and Grover P. Miller. "CYP2E1 Substrate Inhibition." Journal of Biological Chemistry 283, no. 6 (December 4, 2007): 3487–96. http://dx.doi.org/10.1074/jbc.m707630200.
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Tsukamoto, Hide. "CYP2E1 and ALD." Hepatology 32, no. 1 (December 30, 2003): 154–56. http://dx.doi.org/10.1002/hep.510320125.
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Wang, Ting, Huihui Du, Jingsong Ma, Lu Shen, Muyun Wei, Xianglong Zhao, Luan Chen, et al. "Functional characterization of the chlorzoxazone 6-hydroxylation activity of human cytochrome P450 2E1 allelic variants in Han Chinese." PeerJ 8 (July 31, 2020): e9628. http://dx.doi.org/10.7717/peerj.9628.
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Backgrounds Cytochrome P450 (P450) 2E1 is one of the primary enzymes responsible for the metabolism of xenobiotics, such as drugs and environmental carcinogens. The genetic polymorphisms of the CYP2E1 gene in promoter and coding regions have been identified previously in the Han Chinese population from four different geographic areas of Mainland China. Methods To investigate whether genetic variants identified in the CYP2E1 coding region affect enzyme function, the enzymes of four single nucleotide polymorphism (SNP) variants in the coding region (novel c.1009C>T, causing p.Arg337X, where X represents the translational stop codon; c.227G>A, causing p.Arg76His; c.517G>A, yielding p.Gly173Ser; and c.1263C>T, presenting the highest allele frequency), two novel alleles (c.[227G>A;1263C>T] and c.[517G>A;1263C>T]), and the wild-type CYP2E1 were heterologously expressed in COS-7 cells and functionally characterized in terms of expression level and chlorzoxazone 6-hydroxylation activity. The impact of the CYP2E1 variant sequence on enzyme activity was predicted with three programs: Polyphen 2, PROVEAN and SIFT. Results The prematurely terminated p.Arg337X variant enzyme was undetectable by western blotting and inactive toward chlorzoxazone 6-hydroxylation. The c.1263C>T and c.[517G>A;1263C>T] variant enzymes exhibited properties similar to those of the wild-type CYP2E1. The CYP2E1 variants c.227G>A and c.[227G>A;1263C>T] displayed significantly reduced enzyme activity relative to that of the wild-type enzyme (decreased by 42.8% and 32.8%, respectively; P < 0.01). The chlorzoxazone 6-hydroxylation activity of the c.517G>A transfectant was increased by 31% compared with the wild-type CYP2E1 enzyme (P < 0.01). Positive correlations were observed between the protein content and enzyme activity for CYP2E1 (P = 0.0005, r2 = 0.8833). The characterization of enzyme function allelic variants in vitro was consistent with the potentially deleterious effect of the amino acid changes as determined by prediction tools. Conclusions These findings indicate that the genetic polymorphisms of CYP2E1, i.e., c.1009C>T (p.Arg337X), c.227G>A (p.Arg76His), and c.517G>A (p.Gly173Ser), could influence the metabolism of CYP2E1 substrates, such as chlorzoxazone.
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Kumar, Santosh, Bhupesh Singla, Ajay K. Singh, Stacey M. Thomas-Gooch, Kaining Zhi, and Udai P. Singh. "Hepatic, Extrahepatic and Extracellular Vesicle Cytochrome P450 2E1 in Alcohol and Acetaminophen-Mediated Adverse Interactions and Potential Treatment Options." Cells 11, no. 17 (August 23, 2022): 2620. http://dx.doi.org/10.3390/cells11172620.
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Alcohol and several therapeutic drugs, including acetaminophen, are metabolized by cytochrome P450 2E1 (CYP2E1) into toxic compounds. At low levels, these compounds are not detrimental, but higher sustained levels of these compounds can lead to life-long problems such as cytotoxicity, organ damage, and cancer. Furthermore, CYP2E1 can facilitate or enhance the effects of alcohol-drug and drug-drug interactions. In this review, we discuss the role of CYP2E1 in the metabolism of alcohol and drugs (with emphasis on acetaminophen), mediating injury/toxicities, and drug-drug/alcohol-drug interactions. Next, we discuss various compounds and various nutraceuticals that can reduce or prevent alcohol/drug-induced toxicity. Additionally, we highlight experimental outcomes of alcohol/drug-induced toxicity and potential treatment strategies. Finally, we cover the role and implications of extracellular vesicles (EVs) containing CYP2E1 in hepatic and extrahepatic cells and provide perspectives on the clinical relevance of EVs containing CYP2E1 in intracellular and intercellular communications leading to drug-drug and alcohol-drug interactions. Furthermore, we provide our perspectives on CYP2E1 as a druggable target using nutraceuticals and the use of EVs for targeted drug delivery in extrahepatic and hepatic cells, especially to treat cellular toxicity.