Changes in the metabolic profiles of R- and S-warfarin and R- and S-phenprocoumon as a probe to categorize the effect of inducing agents on microsomal hydroxylases.
Changes in the metabolic profiles of R- and S-warfarin and R- and S-phenprocoumon as a probe to categorize the effect of inducing agents on microsomal hydroxylases.
复制标题
R-和S-华法林以及R-和S-苯丙香豆素代谢谱的变化作为探针，对诱导剂对微粒体羟化酶的影响进行分类。
DOI：
10.1016/0006-2952(81)90499-8
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发表时间：
1981
影响因子：
5.8
通讯作者：
W. Trager
中科院分区：
文献类型：
--
作者：
W. Porter;C. Wheeler;W. Trager
The biotransformation ofR- andS-warfarin was examined using liver microsomes prepared from both noninduced rats and rats pretreated with Arochlor 1254, β-napthoflavone (BNF), pregnenolone-16α-carbonitrile (PCN), phenobarbital (PB), and 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD). For comparison, the metabolism of a closely related coumarin anticoagulant,R- andS-phenprocoumon, was determined using the same microsomal preparations. In noninduced microsomes the overall metabolism of warfarin was about five times that of phenprocoumon, with 7-hydroxywarfarin as the principle metabolite followed by the 6-, 4′- and 8-hydroxy derivatives (benzylic hydroxylation was not examined). For phenprocoumon a different regioselectivity was observed with 4′ hydroxylation being the greatest followed by 6-, and 7 and 8 hydroxylation. In the case of warfarin, hydroxylation with noninduced microsomes was either nonstereoselective (4′ hydroxylation) or selective for theR-enantiomer. The metabolic pattern observed for phenprocoumon showed hydroxylation to be either nonstereoselective (7 and 8 hydroxylation) or, in contrast to warfarin, selective for theS-enantiomer. Induction of cytochrome P-450 by Arochlor, BNF, and TCDD produced a similar metabolic pattern for both substrates in which 6 and 8 hydroxylation were greatly increased over control levels. In keeping with the pattern obtained from noninduced microsomes, a reversed stereoselectivity was again observed after induction with these three agents, i.e. warfarin metabolism was selective for theR-enantiomer and phenprocoumon metabolism was selective for theS-enantiomer. Based on cytochrome P-450 levels PCN decreased the metabolism of both substrates while PB had no effect. However, the induction with PB was readily apparent when calculations were performed on a per mg protein basis.
