@article {Woolseydmd.115.065979, author = {Sarah J Woolsey and Sara E. Mansell and Richard B. Kim and Rommel G. Tirona and Melanie D. Beaton}, title = {Cytochrome P450 3A Activity and Expression in Non-Alcoholic Fatty Liver Disease}, elocation-id = {dmd.115.065979}, year = {2015}, doi = {10.1124/dmd.115.065979}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver disease in the Western world given its association to 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, cytochrome P450 3A (CYP3A) in subjects with NAFLD, and 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 non-alcoholic steatohepatitis (NASH) had 2.4-fold higher plasma midazolam levels compared to 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 cells had a 38\% reduction in CYP3A4 activity and 80\% lower CYP3A4 mRNA expression compared to control. CYP3A activity is reduced in human NAFLD in addition to mouse and in vitro cell models of the disease.}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/early/2015/07/29/dmd.115.065979}, eprint = {https://dmd.aspetjournals.org/content/early/2015/07/29/dmd.115.065979.full.pdf}, journal = {Drug Metabolism and Disposition} }