Evidence for mechanism-based inactivation of rat and chick embryo hepatic cytochrome P4501A and P4503A by dihydropyridines, sydnones, and dihydroquinolines

Abstract

Rat hepatic P4501A1 and 3 A 1 2 have been shown previously to be targets for mechanismbased inactivation by the 4-alkyl analogues of 3,5-diethoxycarbonyl-l,4-dihydro-2,4,6-trimethylpyridine (DDC), namely, 4-ethyl DDC and 4-isopropyl DDC. In this study we have shown that rat hepatic P4501A and P4503A are targets for mechanism-based inactivation by the sydnones, 3-[2-(2,4,6-trimethylphenyl)thioethyl]-4-methylsydnone (TTMS) and 3-(2-phenylethyl)-4-methylsydnone (PEMS). The dihydroquinoline, 2,4-diethyl-2-methyl-l,2-dihydroquinoline (DMDQ), caused mechanism-based inactivation of rat hepatic P4501A but not of P4503A. The P4501A isozyme(s) of chick embryo liver was found to share the ability of rat liver P4501A to serve as a target for mechanism-based inactivation by the dihydropyridines, 4-ethyl DDC and 4-isopropyl DDC, the sydnones, TTMS and PEMS, and the dihydroquinoline, DMDO. A P4503A-like isozyme of chick embryo liver shared the ability of the rat liver P4503A isozyme(s) to serve as a target for mechanism-based inactivation by the dihydropyridines, 4-ethyl DDC and 4-isopropyl DDC, and the sydnone, TTMS, but not of the sydnone PEMS. The dihydropyridine, DDC, was found to serve as a mechanism-based inactivator of the chick embryo P4501A isozyme(s), but not of the P4503A isozyme(s), in contrast to its previously reported inactivity with both the rat hepatic P4501A1 and 3 A 1 2 isozymes.