FURANOCOUMARINS AND DRUGS EFFECT ON CYP3A4

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CYP3A4 is the major P450 present in human liver and small bowel epithelial cells (enterocytes). The contribution of enterocyte CYP3A4 to drug elimination is believed to be substantial. However, distinguishing the contributions of the intestinal vs. the liver enzyme, as well as the role of the transporter P-glycoprotein, has been problematic. We have developed experimental techniques that have enabled us to safely study liver and enterocyte CYP3A4 in living people. We have shown that there exists marked inter- and intraindividual variation in the activity of enterocyte CYP3A4. We have also shown that there is generally not a good intraindividual correlation between the relative activities of CYP3A4 in liver and intestine. To further investigate the mechanisms underlying these variations, we have chosen to intensively pursue our observation that some fruit juices (grapefruit juice and Seville orange juice) cause a marked and relatively rapid loss of enterocyte CYP3A4 by a mechanism that does not appear to involve loss of CYP3A4 mRNA. We have shown that 2 juice-derived furanocoumarins (FC s), 6',7'-dihydroxybergamottin (DHB) and a related dimer (FC726), cause selective loss of CYP3A4 in a novel human intestinal (Caco-2) cell monolayer culture system, and that DHB is a mechanism-based inactivator of CYP3A4. However, DHB and FC726 can not fully account for the effects of whole juice, and their effects may not be CYP3A4 selective. We will test the hypothesis that multiple FC s, which are quite ubiquitous in fruits and vegetables, cause mechanism-based inactivation and accelerated intracellular degradation of CYP3A4. To this end, we will characterize the time course of the effects of selected FC s on CYP3A4 and on other major enterocyte P450s in human intestinal microsomes, in our Caco-2 cell system, and in healthy volunteers. We will also determine the effects of selected FC s on rates of synthesis and degradation of CYP3A4 in our cultured cells. Finally, we will test the hypothesis that some oral medication regimens that result in clinically important induction of CYP3A4 in liver do not induce the enzyme in enterocytes. The data obtained from the proposed studies should provide substantial insight into the basis for variations in CYP3A4 activity between people, within a person over time, and between liver and intestine. In addition, the identification of orally administered FC s that specifically ablate CYP3A4 activity in enterocytes (but not liver), or drugs that selectively induce CYP3A4 in liver (but not in enterocytes) would provide powerful research tools to assess the relative contributions of enterocyte and hepatic CYP3A4 to the disposition of xenobiotics in living people.