RIFAMPIN ON HEPATIC CYP3A ACTIVITY IN HEALTHY VOLUNTEERS

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The liver plays an important role in the interaction between man and his chemical environment. A major locus of this interaction in human beings is the liver microsomal hemoprotein cytochrome P450 (CYP3A4). CYP3A4 catalyzes and in many instances may limit the metabolism of over 70% of the clinically used drugs as well as numerous environmental pollutants, carcinogens, and such endogenous substrates as steroid hormones. The CYP3A enzyme in human liver, originally was identified from the pioneering efforts of the celebrated biologist, Hans Selye who identified an inducible activity in rat liver that appeared to play a protective role in animals placed under conditions of chronic stress through physiologic or pharmacologic means. Indeed, there has never been a human identified who lacks CYP3A activity, a finding that suggests that this enzyme plays some essential role in liver metabolism. Measurements of the amounts of CYP3A from human liver biopsies as well as from non-invasive techniques indicate a wide variation among patients, about ten-fold. The amounts of CYP3A in human liver are indeed inducible by such clinically relevant drugs as dexamethasone and the antibiotic rifampin. However, there is no information available on the frequency or magnitude of induction of CYP3A among populations of normal humans. Older literature contains inferences that some people may lack the ability to respond to rifampin with an increase in CYP3A activity. Our hypothesis is that lack of inducibility of CYP3A in the liver may contribute to stress-related diseases due to a failure to metabolically eliminate glucocorticoids and other endogenous products generated under conditions of chronic stress. Rapidly developing information of genetic polymorphisms for families of genes whose products are intimately involved in the activation or inactivation of toxic chemicals emphasize the importance of developing information on interindividual differences in susceptibility. Although the CYP3A enzymes exhibit a wide range of interindividual variability in their levels in liver, no genetic component reponsible for polymorphism in their expression has been confirmed. Critically needed for evaluation of the clinical importance of putative regulatory regions of this gene is phenotypic identification of humans who are either over or under expressers with regards to its drug mediated inducibility. In this study we propose to: 1) use a non-invasive measure of liver CYP3A activity, specifically the erythromycin breath test, to determine the amounts of CYP3A in the basal steady state and after induction by orally administered rifampin in normal human volunteers, 2) provide a confirmation of CYP3A induction in these volunteers by measuring changes in rifampin half-life before and after one week of treatment with rifampin, and 3) analyze DNA isolated from individuals phenotyped for CYP3A4 activity in order to associate a specific CYP3A4 genotype with a specific CYP3A4 phenotype.