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Vol. 31, Issue 5, 533-539, May 2003

Regulation of CYP3A4 Expression in Human Hepatocytes by Pharmaceuticals and Natural Products

Judy L. Raucy

California Toxicology Research Institute, Carlsbad, California

Human CYP3A4 metabolizes a majority of clinically important substrates at variable rates. Accounting for these unpredictable rates is the wide variation noted in expression of this enzyme that is due, in part, to xenobiotic exposure. We used primary cultures of human hepatocytes from 17 individuals to assess the inducibility of CYP3A4 mRNA by prototypical inducers, dietary flavonoids, and botanicals. Those agents producing the greatest mRNA accumulation were 10 µM RIF (699 ± 307% of control levels) 100 µM phenytoin (707 ± 188% of control), 1 mM phenobarbital (536 ± 207% of control), and 100 µM omeprazole (404 ± 8% of control). Various concentrations of RIF were found to exhibit a typical dose-response curve for CYP3A4 mRNA content. A reporter gene assay using the human pregnane X receptor (hPXR) and promoter regions of CYP3A4 transiently transfected into HepG2 cells, exhibited inductive properties by the aforementioned therapeutics that were similar to those observed in hepatocytes. Several flavonoids including quercetin, resveratrol, and curcumin were also examined for their ability to induce CYP3A4 in human hepatocytes. Only quercetin produced accumulation of CYP3A4 mRNA (230 ± 73% of control). When examined in a reporter gene assay, this flavonoid exhibited negligible increases in luciferase activity suggesting that quercetin induced CYP3A4 by mechanisms that may not involve PXR. We also examined the effects of herbals on CYP3A4 expression in human hepatocytes. Grapeseed extract, ginseng, silymarin, and kava-kava produced 270 ± 73, 155 ± 83, 100 ± 10, and 386 ± 185% of control CYP3A4 mRNA, respectively. Of these botanicals only kava-kava produced enhanced luciferase activity (11.6 ± 2.1 fold above DMSO treated cells). Such results indicate that kava-kava required PXR to mediate CYP3A4 induction. Collectively, results demonstrated that several botancials induce CYP3A4, suggesting the potential for drug-herbal interactions.

Copyright © 2003 by The American Society for Pharmacology and Experimental Therapeutics


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