Kimmett S M, McNamee J P, Denofreo R T, Marks G S
Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada.
Biochem Pharmacol. 1994 Jun 1;47(11):2069-78. doi: 10.1016/0006-2952(94)90083-3.
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.
先前已表明，大鼠肝脏中的细胞色素P4501A1和3A1/2是3,5 - 二乙氧基羰基 - 1,4 - 二氢 - 2,4,6 - 三甲基吡啶（DDC）的4 - 烷基类似物（即4 - 乙基DDC和4 - 异丙基DDC）基于机制失活的靶点。在本研究中，我们已表明大鼠肝脏中的细胞色素P4501A和P4503A是 sydnones（3 - [2 - (2,4,6 - 三甲基苯基)硫代乙基] - 4 - 甲基sydnone（TTMS）和3 - (2 - 苯乙基) - 4 - 甲基sydnone（PEMS））基于机制失活的靶点。二氢喹啉2,4 - 二乙基 - 2 - 甲基 - 1,2 - 二氢喹啉（DMDQ）可导致大鼠肝脏细胞色素P4501A基于机制的失活，但对P4503A无此作用。已发现鸡胚肝脏的P4501A同工酶具有与大鼠肝脏P4501A相同的能力，可作为二氢吡啶类（4 - 乙基DDC和4 - 异丙基DDC）、sydnones（TTMS和PEMS）以及二氢喹啉（DMDQ）基于机制失活的靶点。鸡胚肝脏中一种类似P4503A的同工酶具有与大鼠肝脏P4503A同工酶相同的能力，可作为二氢吡啶类（4 - 乙基DDC和4 - 异丙基DDC）以及sydnone（TTMS）基于机制失活的靶点，但对sydnone PEMS无此作用。与先前报道的对大鼠肝脏P4501A1和3A1/2同工酶均无活性相反，已发现二氢吡啶DDC可作为鸡胚P4501A同工酶基于机制的失活剂，但对P4503A同工酶无此作用。
