METABOLISM OF DELTA(9)-TETRAHYDROCANNABINOL BY CYTOCHROME-P450 ISOZYMES PURIFIED FROM HEPATIC MICROSOMES OF MONKEYS
METABOLISM OF DELTA(9)-TETRAHYDROCANNABINOL BY CYTOCHROME-P450 ISOZYMES PURIFIED FROM HEPATIC MICROSOMES OF MONKEYS
复制标题
DOI：
10.1016/0024-3205(95)00193-a
复制
发表时间：
1995-05-05
期刊：
影响因子：
6.1
通讯作者：
YOSHIMURA, H
中科院分区：
文献类型：
--
作者：
MATSUNAGA, T;IWAWAKI, Y;YOSHIMURA, H
在猴肝微粒体中形成的δ（9）-四氢大麻酚（δ（9）-THC）最丰富的代谢物是11-OH-δ（9）-THC，其次是8 α-OH-、8 β-OH-和3 '-OH-δ（9）-THC。从猴肝微粒体中纯化了两种细胞色素P450同工酶，P450 RM-A和P450 JM-C，分子量为51，000。在重组系统中，P450 RM-A形成11-OH-、8 α-OH-、8 β-OH-和3 ′-OH-δ（9）-THC的活性分别比肝微粒体的相应活性高19、40、22和10倍。P450 JM-C形成3 ′-OH-δ（9）-THC的活性比P450 RM-A高10倍，而11-和8 α-羟基化的两种同工酶的活性没有太大差异，P450 RM-A中的8 β-羟基化活性比P450 JM-C高14倍。抗P450 RM-A和P450 JM-C抗体分别显著抑制11-OH-和8 α-OH-δ（9）-THC以及3 '-OH-δ（9）-THC的微粒体形成。这些结果表明，P450 RM-A和P450 JM-C是主要的同工酶，分别负责在猴子中形成11-OH-和8 α-OH-δ（9）-THC和3 ′-OH-δ（9）-THC。
The most abundant metabolite of Delta(9)-tetrahydrocannabinol (Delta(9)-THC) formed with hepatic microsomes of monkeys was 11-OH-Delta(9)-THC, followed by 8 alpha-OH-, 8 beta-OH- and 3'-OH-Delta(9)-THCs. Two cytochrome P450 isozymes, P450RM-A and P450JM-C, were purified from monkey hepatic microsomes and found to have a molecular weight of 51,000. In the reconstituted system, the activities of P450RM-A towards formation of 11-OH-, 8 alpha-OH-, 8 beta-OH- and 3'-OH-Delta(9)-THCs were 19-, 40-, 22- and 10-fold higher, respectively, than the corresponding activities of the hepatic microsomes. The activity of P450JM-C towards formation of 3'-OH-Delta(9)-THC was 10-fold higher than that of P450RM-A, while the activities of both isozymes for 11- and 8 alpha-hydroxylation were not so much different and the 8 beta-hydroxylation activity was 14-fold higher in P450RM-A than in P450JM-C. Antibodies against P450RM-A and P450JM-C markedly inhibited the microsomal formation of 11-OH- and 8 alpha-OH-Delta(9)-THCs, and 3'-OH-Delta(9)-THC, respectively. These results suggest that P450RM-A and P450JM-C are major isozymes responsible for the formation of 11-OH- and 8 alpha-OH-Delta(9)-THCs, and 3'-OH-Delta(9)-THC, respectively, in monkeys.