In vivo cytochrome P450 activity alterations in diabetic nonalcoholic steatohepatitis mice

Hui Li, John D. Clarke, Anika L. Dzierlenga, John Bear, Michael J. Goedken, Nathan J Cherrington

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere21840
JournalJournal of Biochemical and Molecular Toxicology
Volume31
Issue number2
DOIs
StatePublished - Feb 1 2017

Fingerprint

Cytochrome P-450 Enzyme System
Metabolism
Pharmacokinetics
Losartan
Omeprazole
Caffeine
Pharmaceutical Preparations
Non-alcoholic Fatty Liver Disease
Protein Isoforms
Human Activities
Messenger RNA
Substrates
Liver
Proteins

Keywords

  • Cytochrome P450
  • methionine and choline deficient
  • nonalcoholic steatohepatitis
  • variable drug responses

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

In vivo cytochrome P450 activity alterations in diabetic nonalcoholic steatohepatitis mice. / Li, Hui; Clarke, John D.; Dzierlenga, Anika L.; Bear, John; Goedken, Michael J.; Cherrington, Nathan J.

In: Journal of Biochemical and Molecular Toxicology, Vol. 31, No. 2, e21840, 01.02.2017.

Research output: Contribution to journalArticle

Li, Hui ; Clarke, John D. ; Dzierlenga, Anika L. ; Bear, John ; Goedken, Michael J. ; Cherrington, Nathan J. / In vivo cytochrome P450 activity alterations in diabetic nonalcoholic steatohepatitis mice. In: Journal of Biochemical and Molecular Toxicology. 2017 ; Vol. 31, No. 2.
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