title: CYP3A Activity and Expression in Nonalcoholic Fatty Liver Disease.
abstract: Nonalcoholic fatty liver disease (NAFLD) is the leading cause of liver disease in the Western world, given its association with obesity, type 2 diabetes, and dyslipidemia. Medications are widely used in NAFLD to manage comorbid conditions, and there is significant interest in developing new drug therapies to treat the disease. Despite this, little is known about the effects of NAFLD on drug metabolism. We examined the activity and expression of the major drug-metabolizing enzyme subfamily, CYP3A, in subjects with NAFLD as well as in mouse and cellular models. CYP3A activity was determined in healthy volunteers and subjects with biopsy-proven NAFLD by oral midazolam phenotyping and measurement of plasma 4β-hydroxycholesterol, an endogenous metabolic biomarker. CYP3A4 transcriptional activity, metabolic activity, and expression were also assessed in a mouse and cellular model of NAFLD. Subjects with nonalcoholic steatohepatitis (NASH) had 2.4-fold higher plasma midazolam levels compared with controls. Plasma 4β-hydroxycholesterol was 51% and 37% lower than controls in subjects with simple steatosis and NASH, respectively. Fibrosis was associated with 57% lower plasma 4β-hydroxycholesterol levels than controls. Furthermore, hepatic CYP3A4 mRNA expression in NASH was 69% lower than control livers. CYP3A4 gene luciferase activity in the livers of NAFLD mice was 38% lower than that of controls. Lipid-loaded Huh7 human hepatoma cells had a 38% reduction in CYP3A4 activity and 80% lower CYP3A4 mRNA expression compared with the control. CYP3A activity is reduced in human NAFLD in addition to mouse and in vitro cell models of the disease.
authors.affiliation: Divisions of Clinical Pharmacology (S.J.W, S.E.M, R.B.K, R.G.T.) and Gastroenterology (M.D.B), Departments of Medicine (S.J.W, S.E.M, R.B.K, R.G.T., M.D.B.) and Physiology and Pharmacology (S.J.W, R.B.K, R.G.T.), Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Woolsey
authors.affiliation: Divisions of Clinical Pharmacology (S.J.W, S.E.M, R.B.K, R.G.T.) and Gastroenterology (M.D.B), Departments of Medicine (S.J.W, S.E.M, R.B.K, R.G.T., M.D.B.) and Physiology and Pharmacology (S.J.W, R.B.K, R.G.T.), Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
authors.forename: Sara E
authors.initials: SE
authors.lastname: Mansell
authors.affiliation: Divisions of Clinical Pharmacology (S.J.W, S.E.M, R.B.K, R.G.T.) and Gastroenterology (M.D.B), Departments of Medicine (S.J.W, S.E.M, R.B.K, R.G.T., M.D.B.) and Physiology and Pharmacology (S.J.W, R.B.K, R.G.T.), Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Kim
authors.affiliation: Divisions of Clinical Pharmacology (S.J.W, S.E.M, R.B.K, R.G.T.) and Gastroenterology (M.D.B), Departments of Medicine (S.J.W, S.E.M, R.B.K, R.G.T., M.D.B.) and Physiology and Pharmacology (S.J.W, R.B.K, R.G.T.), Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
authors.forename: Rommel G
authors.initials: RG
authors.lastname: Tirona
authors.affiliation: Divisions of Clinical Pharmacology (S.J.W, S.E.M, R.B.K, R.G.T.) and Gastroenterology (M.D.B), Departments of Medicine (S.J.W, S.E.M, R.B.K, R.G.T., M.D.B.) and Physiology and Pharmacology (S.J.W, R.B.K, R.G.T.), Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada melanie.beaton@lhsc.on.ca.
authors.forename: Melanie D
authors.initials: MD
authors.lastname: Beaton
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis* / Q000235:genetics; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000201:enzymology* / Q000473:pathology
chemical_list: C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A