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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    • "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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    • "This effect may be attributed to the ability of limonin to inhibit CYP3A4 activity (Iwata et al. 2005). Previous studies indicated that hepatic steatosis is associated with decreased hepatic CYP3A4 activity in humans via posttranslational mechanism (Kolwankar et al. 2007). "
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    ABSTRACT: Toll-like receptors have been implicated in inflammation and injury in various tissues and organs including the liver. We have investigated the effects of limonin isolated from the dichloromethane fraction of the seeds of bittersweet orange (Citrus aurantium var. bigaradia) in two dose levels (50 and 100 mg/kg) against D-galactosamine (D-GalN)-induced liver toxicity in comparison with standard silymarin treatment on Toll-like receptors expression and hepatic injury, using a well-established rat model of acute hepatic inflammation. The limonoids in the seeds of bittersweet orange were identified. Oral administration of limonin before D-GalN injection, significantly attenuated markers of hepatic damage (elevated liver enzyme activities and total bilirubin) and hepatic inflammation (TNF-α, infiltration of neutrophils), oxidative stress and expression of TLR-4 but not TLR-2 in D-GalN-treated rats. Limonin effects were similar in most aspects to that of the lignan silymarin. The higher dose of limonin (100 mg/kg) performed numerically better for AST and bilirubin, and both doses yielded similar results for ALT and GGT. While the lower dose of limonin (50 mg/kg) performed better against oxidative stress and liver structural damage as compared to the higher dose. Limonin exerts protective effects on liver toxicity associated with inflammation and tissue injury via attenuation of inflammation and reduction of oxidative stress.
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