Background & Aims: Comorbidities associated with nonalcoholic fatty liver often require therapy with medications (eg, statins) metabolized by cytochrome P-450 3A (CYP3A). There is significant interindividual variability in CYP3A expression. However, human studies that systematically examined the relationship between hepatic steatosis and hepatic CYP3A activity are lacking. Methods: The relationship of hepatic CYP3A activity with several variables including hepatic steatosis, CYP3A4 protein content, CYP3A4 mRNA expression, CYP3A5 genotype, and its mRNA expression was investigated in human liver samples (n = 49). CYP3A activity was quantified from liver microsomes by using testosterone as a probe, and hepatic steatosis was defined to be present if >5% of hepatocytes had large globules of intracellular fat displacing the nucleus. Results: The mean ± standard error hepatic CYP3A activity of the study group was 3156 ± 2794 pmol · min-1 · mg-1 of protein, and it was not associated with age, gender, medicinal use, CYP3A5 or pregnane xenobiotic receptor mRNA expression, or CYP3A5 genotype. Twenty-four liver samples with steatosis had significantly lower hepatic CYP3A activity than 25 liver samples without steatosis (1978 ± 299 vs 4287 ± 659 pmol · min-1 · mg-1 of protein; P = .003). This difference persisted even after controlling for relevant covariates in the multivariate analysis (P = .04). However, CYP3A4 protein content was not different between the 2 groups (6 ± 1.3 vs 8.5 ± 2.2 pmol/mg protein; P = .3). There was a significant negative relationship between severity of steatosis and hepatic CYP3A activity (P = .01). Conclusions: Hepatic steatosis is associated with decreased hepatic CYP3A activity in humans via post-translational mechanism. Further studies are needed to confirm our findings.
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