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Human cytochromes P4503A (CYP3A) metabolize numerous therapeutic agents, bioactivate environmental xenobiotics, and are induced by drugs and pesticides. Because there is large interindividual variation in basal and inducible expression of CYP3A, that affects therapeutic outcome and could serve as a susceptibility marker for environmentally caused diseases, the factors that regulate CYP3A are under intense investigation. Our studies have established that the product of the multidrug resistance gene (MDR1), the drug efflux transporter P-glycoprotein (Pgp), influences the oral absorption of one CYP3A inducer, its intracellular disposition and thus the extent to which this drug induces CYP3A. Because Pgp transports steroids and other structurally diverse xenobiotics that are CYP3A substrates, inhibitors and inducers our lab is testing whether Pgp is a determinant of basal CYP3A expression and the magnitude of CYP3A induction by many other structurally unrelated xenobiotics. Using novel cell model systems and mice nullizygous formdr1a/1b/Pgp (mdr1a/1b (-/-) mice) the capabilities of mouse and human MDR/Pgp to transport some CYP3A inducers, substrates and inhibitors are also ongoing. We are also testing whether Pgp, by influencing the intracellular concentration of CYP3A substrates, influences the rate and extent of CYP3A-mediated metabolism using novel cell lines which form polarized epithelium in culture and stably express functional CYP3A4 and Pgp. In total, our lab examines the nature of the interaction between CYP3A substrates and inducers at the level of their common membrane transporter, Pgp, and the ramifications of these Pgp interactions on CYP3A mediated metabolism and the CYP3A inductive response.
Last update: April 2003