title: In vivo cytochrome P450 activity alterations in diabetic nonalcoholic steatohepatitis mice.
abstract: Nonalcoholic steatohepatitis (NASH) has been identified as a source of significant interindividual variation in drug metabolism. A previous ex vivo study demonstrated significant changes in hepatic Cytochrome P450 (CYP) activity in human NASH. This study evaluated the in vivo activities of multiple CYP isoforms simultaneously in prominent diabetic NASH mouse models. The pharmacokinetics of CYP selective substrates: caffeine, losartan, and omeprazole changed significantly in a diabetic NASH mouse model, indicating attenuation of the activity of Cyp1a2 and Cyp2c29, respectively. Decreased mRNA expression of Cyp1a2 and Cyp2c29, as well as an overall decrease in CYP protein expression, was found in the diabetic NASH mice. Overall, these data suggest that the diabetic NASH model only partially recapitulates the human ex vivo CYP alteration pattern. Therefore, in vivo determination of the effects of NASH on CYP activity should be conducted in human, and more appropriate models are required for future drug metabolism studies in NASH.
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, 85721, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, 85721, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Clarke
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, 85721, USA.
authors.forename: Anika L
authors.initials: AL
authors.lastname: Dzierlenga
authors.affiliation: Statistical Consulting Lab, Univeristy of Arizona, Tucson, AZ, 85721, USA.
authors.forename: John
authors.initials: J
authors.lastname: Bear
authors.affiliation: Translational Sciences, Research Pathology Services, Rutgers University, New Brunswick, NJ, 08854, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Goedken
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, 85721, USA.
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Cherrington
mesh_terms: D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D008099:Liver / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy / Q000201:enzymology*; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System
keywords: Cytochrome P450; methionine and choline deficient; nonalcoholic steatohepatitis; variable drug responses