Roles of cytochrome P-450 enzymes in chemical carcinogenesis and cancer chemotherapy.
Roles of cytochrome P-450 enzymes in chemical carcinogenesis and cancer chemotherapy.
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作者：
F. Guengerich
涉及化学致癌物代谢的研究在细胞色素P-450酶系统的发现和初步表征中非常重要。米莱尔及其同事鉴定了参与偶氮染料生物转化的NADPH依赖性微粒体酶（1，2）。这些反应，还原和混合功能氧化，也被发现在许多其他致癌物，以及药物和类固醇的加工中很重要。随后的工作确定血红素蛋白P-4503是参与微粒体混合功能氧化的末端氧化酶（3，4）。其他早期的研究表明，给动物施用许多不同的化学物质可以改变致癌物的代谢（5-7）。正如我们现在所知道的，存在许多形式的P-450，这些酶的表达受到给予动物的化合物的影响。对大鼠给予致癌的多环烃3-甲基胆蒽并分析肝微粒体，提供了一些早期证据，表明存在多种形式的P-450（8，9）。从那时起，大量的努力集中在了解这些P-450酶的生物化学方面，即它们如何催化反应以及它们的表达如何调节。虽然关于P-450蛋白的大部分焦点涉及它们对类固醇和药物代谢的贡献，但仍有相当大的努力致力于了解P-450在致癌物代谢中的作用。P-450酶的特性在此不再详细讨论。4微粒体酶存在于大多数组织中，但集中在肝脏中。它们都在450 nm附近具有特征性的一氧化亚铁复合物Soret峰，montimene分子量约为50，000，并接受来自黄素蛋白NADPH-P-450还原酶的电子。从大鼠肝脏中分离出近20种不同的P-450蛋白，它们似乎都是不同的基因产物。个别蛋白质的水平会因施用或暴露于多种化学物质而改变，其中许多本身就是致癌物（包括肿瘤引发剂，如多环烃和肿瘤促进剂，如苯巴比妥）。线粒体P-450接受铁蛋白的电子，似乎主要参与合成代谢类固醇代谢，尽管已经提出了一些致癌物氧化作用的证据（14）。一些评论和专著涉及P-450酶的催化机制和调节的各个方面
Studies involving the metabolism of chemical carcinogens were important in the discovery and initial characterization of the cytochrome P-450 enzyme system. The Millers and their associates identified NADPH-dependent microsomal enzymes involved in the biotransformation of azo dyes (1, 2). These reactions, reduction and mixed-function oxidation, were also found to be important in the processing of many other carcin ogens, as well as drugs and steroids. Subsequent work led to the identification of the hemoprotein P-4503 as the terminal oxidase involved in such microsomal mixed-function oxidations (3,4). Other early studies revealed that administration of many different chemicals to animals could alter the metabolism of carcinogens (5-7). As we know now, many forms of P-450 exist and the expression of these enzymes is influenced by the com pounds which are given to the animals. Administration of the carcinogenic polycyclic hydrocarbon 3-methylcholanthrene to rats and analysis of the liver microsomes provided some of the early evidence that multiple forms of P-450 exist (8, 9). Since that time, a great deal of effort has been concentrated upon understanding the biochemistry of these P-450 enzymes, in terms of how they catalyze reactions and how their expression is regulated. Although much of the focus regarding P-450 proteins has involved their contributions to the metabolism of steroids and drugs, considerable effort is still directed towards understanding the roles of P-450s in carcinogen metabolism. The characteristics of P-450 enzymes will not be reviewed at length here.4 The microsomal enzymes are found in most tissues but are concentrated in liver. All have characteristic ferrouscarbon monoxide complex Soret peaks near 450 nm, have montimene molecular weights of about 50,000, and accept electrons from the flavoprotein NADPH-P-450 reducÃ-ase. Nearly 20 different P-450 proteins have been isolated from rat liver and all appear to be distinct gene products. Levels of the individual proteins are altered by administration of or exposure to a wide variety of chemicals, many of which are carcinogens themselves (including tumor initiators such as the polycyclic hydrocarbons and tumor promoters such as phénobarbital). Mitochondrial P-450s accept electrons from ferridoxins and seem to be primarily involved in anabolic steroid metabolism, although some evidence for roles in carcinogen oxidation has been presented (14). Several reviews and monographs deal with various aspects of the catalytic mechanisms and regulation of the P-450 enzymes