Association Between Nonalcoholic Hepatic Steatosis and Hepatic Cytochrome P-450 3A Activity

Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association (Impact Factor: 7.9). 04/2007; 5(3):388-93. DOI: 10.1016/j.cgh.2006.12.021
Source: PubMed


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.
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.
The mean +/- standard error hepatic CYP3A activity of the study group was 3156 +/- 2794 pmol x min(-1) x 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 x min(-1) x 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).
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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    • "Notably, obesity and NAFLD in rodents and humans are associated with different alterations in the activity of hepatic enzymes involved in drug metabolism including cytochromes P450 (CYPs), UDP-glucuronosyltransferases and transporters (Brill et al., 2012; Canet et al., 2015). More specifically, these dysmetabolic disorders are associated with higher CYP2E1 activity, lower CYP3A4 activity and increased capacity of glucuronide conjugation for different drugs such as APAP and lorazepam (Aubert et al., 2011; Brill et al., 2012; Chalasani et al., 2003; Emery et al., 2003; Kolwankar et al., 2007; Woolsey et al., 2015). "
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    • "In fact, it is known that the expression of CYPs is altered in the liver of humans and animal models with diabetes mellitus, obesity and/or hepatic steatosis . With regard to humans, decreased CYP3A activity is associated with hepatic steatosis (Kolwankar et al., 2007). Moreover, CYP3A activity and CYP3A4 mRNA level are reduced and CYP2E1 activity is increased in the liver of subjects with diabetes (Dostalek et al., 2011). "
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