OXIDATION OF DIHYDROPYRIDINE CALCIUM-CHANNEL BLOCKERS AND ANALOGS BY HUMAN LIVER CYTOCHROME-P-450 IIIA4
OXIDATION OF DIHYDROPYRIDINE CALCIUM-CHANNEL BLOCKERS AND ANALOGS BY HUMAN LIVER CYTOCHROME-P-450 IIIA4
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DOI：
10.1021/jm00110a012
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发表时间：
1991-06-01
影响因子：
7.3
通讯作者：
BERNTSSON, P
中科院分区：
文献类型：
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作者：
GUENGERICH, FP;BRIAN, WR;BERNTSSON, P
研究了21种不同的4-取代2，6-dimethyl-3-(alkoxycarbonyl)-1，4-dihydropyridines对人肝微粒体细胞色素P-450氧化为吡啶类化合物的影响。针对P-450 IIIA4的抗体对硝苯地平和非洛地平的微体氧化有相同程度的抑制作用，西咪替丁和基于机理的灭活剂孕二烯也是如此。按摩尔计算，孕二烯是西咪替丁的大约10(3)倍有效的抑制剂。当比较不同人肝微粒体制剂中1，4-二氢吡啶的氧化速率时，除4位不含取代基的衍生物和N1-CH3衍生物外，其余均高度相关。在酵母中表达了P-4.50 IIIA4基因克隆，并将部分纯化的蛋白用于含有NADPH-细胞色素P-450还原酶和细胞色素b5的重组系统中。该体系催化了所有1，4-二氢吡啶的氧化，只有两个在肝微粒体中的相关性较差。主成分分析支持这一观点，即大多数反应是由酵母P-450 IIIA4制剂中的同一种酶和不同的人肝微粒体制剂中的同一种酶催化的，或者是由一种密切相关的酶催化的，该酶具有几乎相同的催化专一性和调节特性。结果表明，P-450 IIIA4酶可能是参与大多数(但不是全部)1，4-二氢吡啶类药物脱氢反应的主要人类催化剂。
A series of 21 different 4-substituted 2,6-dimethyl-3-(alkoxycarbonyl)-1,4-dihydropyridines was considered with regard to oxidation to pyridine derivatives by human liver microsomal cytochrome P-450 (P-450). Antibodies raised against P-450 IIIA4 inhibited the microsomal oxidation of nifedipine and felodipine to the same extent, as did cimetidine and the mechanism-based inactivator gestodene. Gestodene was approximately 10(3) times more effective an inhibitor than cimetidine, on a molar basis. When rates of oxidation of the 1,4-dihydropyridines were compared to each other in different human liver microsomal preparations, all were highly correlated with each other with the exceptions of a derivative devoid of a substituent at the 4-position and an N1-CH3 derivative. A P-4.50 IIIA4 cDNA clone was expressed in yeast and the partially purified protein was used in reconstituted systems containing NADPH-cytochrome P-450 reductase and cytochrome b5. This system catalyzed the oxidation of all of the 1,4-dihydropyridines except the two for which poor correlation was seen in the liver microsomes. Principal component analysis supported the view that most of these reactions were catalyzed by the same enzyme in the yeast P-450 IIIA4 preparation and in the different human liver microsomal preparations, or by a closely related enzyme showing nearly identical properties of catalytic specificity and regulation. The results indicate that the enzyme P-450 IIIA4 is probably the major human catalyst involved in the formal dehydrogenation of most but not all 1,4-dihydropyridine drugs.