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 3,5-diethoxycarbonyl-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 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-1,2-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, DMDQ. 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 3A1/2 isozymes.
Kimmett
S M
SM
Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada.
McNamee
J P
JP
Denofreo
R T
RT
Marks
G S
GS
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D002642:Chick Embryo; D019363:Cytochrome P-450 CYP1A1; D019392:Cytochrome P-450 CYP2E1; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004095:Dihydropyridines / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D010088:Oxidoreductases / Q000096:biosynthesis; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013558:Sydnones / Q000494:pharmacology*
D065607:Cytochrome P-450 Enzyme Inhibitors; D004095:Dihydropyridines; D011804:Quinolines; D013558:Sydnones; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating