P-GLYCOPROTEIN - A MAJOR DETERMINANT OF RIFAMPICIN-INDUCIBLE EXPRESSION OF CYTOCHROME P4503A IN MICE AND HUMANS

The P-glycoprotein (Pgp) efflux pump can influence the hepatocellular concentration of xenobiotics that are modulators and substrates of cyt ochrome P4503A (CYP3A). We tested the hypothesis that Pgp is a determi nant of drug-inducible expression of CYP3A. The magnitude of CYP3A ind uction by rifampicin was compared in the human parental colon carcinom a cell line LS 180/WT (wild type) and in two derivative clones overexp ressing the human multidrug resistance gene MDR1 (also designated PGY1 ) because of either drug selection (LS 180/ADR) or transfection with M DR1 cDNA (LS 180/MDR). In both MDR1 cDNA-overexpressing clones, rifamp icin induction of CYP3A mRNA and protein was decreased and required gr eater rifampicin concentrations compared with parental cells. The role of Pgp in regulation of CYP3A expression in vivo was analyzed in mice carrying a targeted disruption of the mdr1a mouse gene. Oral treatmen t with increasing doses of rifampicin resulted in elevated drug levels in the livers of mdr1a (-/-) mice compared with mdr1a (+/+) mice at a ll doses. Consistent with the enhanced accumulation of rifampicin in m dr1a (-/-) mice, lower doses of rifampicin were required for induction of CYP3A proteins, and the magnitude of CYP3A induction was greater a t all doses of rifampicin in mdr1a (-/-) mice compared with mdr1a (+/) mice. We conclude that Pgp-mediated transport is a critical element influencing the CYP3A inductive response.