Relative contribution of various forms of cytochrome P450 to the metabolism of benzo[a]pyrene by human liver microsomes.
Relative contribution of various forms of cytochrome P450 to the metabolism of benzo[a]pyrene by human liver microsomes.
复制标题
各种形式的细胞色素 P450 对人肝微粒体苯并[a]芘代谢的相对贡献。
DOI：
10.1093/carcin/10.10.1815
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发表时间：
1989
期刊：
影响因子：
4.7
通讯作者：
Wolf,CR
中科院分区：
文献类型：
--
作者：
Hall,M;Forrester,LM;Parker,DK;Grover,PL;Wolf,CR
多种细胞色素P450与苯并[a]芘（BP）的肝代谢有关，包括组成型表达和高度诱导型表达。在本研究中，BP代谢为有机溶剂可溶性衍生物的8种形式的细胞色素P450从大鼠肝脏和一系列的11个人肝微粒体样品进行了研究。评价了特定P450形式对人肝脏代谢的相对贡献。观察到总有机溶剂可溶性BP代谢物形成的4倍变化，以及研究的三个个体之间这种代谢的区域和立体选择性的差异。从五个基因亚家族的细胞色素P450的表达水平，通过Western印迹分析确定，并没有表现出任何相关性与BP代谢率的有机溶剂可溶性衍生物在这些肝脏。在三个肝脏中未观察到代谢降低，其中未表达debrisoqulne P450（P450 IID 1）或丁呋洛尔1-羟化酶活性较低。在所测试的六种不同的针对大鼠肝P450形式的抗体中，仅针对P450 s的MCla（P450 IA 2）、MClb（P450 IA 1）和UT（P450 IIA 1）的抗体持续抑制BP代谢。这种抑制作用通常是有限的，很少超过30%。然而，细胞色素P450 PB（P450）的抗体确实抑制了一名接受苯妥英药物的个体肝脏微粒体组分在BP的4，5-和9，10-位置形成代谢物。这些数据表明，人肝脏中的几种形式的P450参与BP的代谢，组成型表达和诱导型表达在人体内的分布中都很重要。
A variety of cytochromes P450 have been implicated in the hepatic metabolism of benzo[a]pyrene (BP), including forms that are constitutively expressed and those that are highly inducible. In the present study the metabolism of BP to organic solvent-soluble derivatives by eight forms of cytochrome P450 isolated from rat liver and by a series of 11 human liver microsomal samples was investigated. The relative contribution of specific P450 forms to the human hepatic metabolism was evaluated. A 4-fold variation in formation of total organic solvent-soluble BP metabolites was observed, as well as differences in the regio- and stereo-selectivity of this metabolism between the three individuals studied. The levels of expression of cytochromes P450 from five gene sub-families, as determined by Western blot analysis, did not show any correlation with the rate of BP metabolism to organic solvent-soluble derivatives in these livers. No reduction in metabolism was observed in three livers in which either the debrisoqulne P450 (P450IID1) was not expressed or bufuralol 1-hydroxylase activity was low. Of six different antibodies to forms of rat liver P450 tested, only those to P450s MCla(P450IA2), MClb(P450IA1) and UT (P450IIA1) consistently inhibited BP metabolism. This inhibition was generally limited and rarely exceeded 30%. An antibody to cytochrome P450 PB (P450 did, however, inhibit the formation of metabolites at the 4,5- and 9,10-positions of BP by microsomal fractions of livers from one individual who had been receiving the drug phenytoin. These data indicate that several forms of P450 in human liver are involved in the metabolism of BP and that both constitutively expressed as well as inducible forms are important in its disposition in man.