EVIDENCE FOR MECHANISM-BASED INACTIVATION OF RAT AND CHICK-EMBRYO HEPATIC CYTOCHROME P4501A AND P4503A BY DIHYDROPYRIDINES, SYDNONES, AND DIHYDROQUINOLINES

Rat hepatic P4501A1 and 3A1/2 have been shown previously to be targets for mechanism-based inactivation by the 4-alkyl analogues of ethoxyca rbonyl-1,4-dihydro-2,4,6-trimethylpyridine (DDC), namely, 4-ethyl DDC and 4-isopropyl DDC. In this study we have shown that rat hepatic P450 1A and P4503A are targets for mechanism-based inactivation by the sydn ones, -(2,4,6-trimethylphenyl)thioethyl]-4-methylsydnone (TTMS) and 3- (2-phenylethyl)-4-methylsydnone (PEMS). The dihydroquinoline, 2,4-diet hyl-2-methyl-1,2-dihydroquinoline (DMDQ), caused mechanism-based inact ivation 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 P45 01A to serve as a target for mechanism-based inactivation by the dihyd ropyridines, 4-ethyl DDC and 4-isopropyl DDC, the sydnones, TTMS and P EMS, and the dihydroquinoline, DMDQ. A P4503A-like isozyme of chick em bryo liver shared the ability of the rat liver P4503A isozyme(s) to se rve as a target for mechanism-based inactivation by the dihydropyridin es, 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 m echanism-based inactivator of the chick embryo P4501A isozyme(s), but not of the P4503A isozyme(s), in contrast to its previously reported i nactivity with both the rat hepatic P4501A1 and 3A1/2 isozymes.