Xenobiotic-Metabolizing Enzymes

在哺乳动物中，存在大量代谢药物和其他外源性物质的酶。细胞色素P450是参与大多数治疗用药物代谢的这些酶中最重要的酶之一。此外，P450还催化化学致癌物的代谢活化。参与异生物质代谢的P450存在于CYP 1、CYP 2和CYP 3家族中。这些家族中的每一个都由两个或多个亚家族组成。P450可以在体外代谢活化毒素和原致癌物，这一事实意味着它们与毒性和癌症有关。然而，目前尚不清楚P450是否是化学品在完整动物中的毒性和致癌性所必需的。提示P450在癌症病因学中的作用的唯一实验是细胞培养中的间接化学诱导转化测定和涉及Ah基因座的小鼠遗传实验。没有直接的证据可以证明P450是完整动物模型系统中致癌所必需的。为了评估P450对急性化学毒性和化学致癌过程的潜在贡献，并确定它们在哺乳动物发育和生理稳态中的作用（如果有的话），产生了P450缺失小鼠。还制备了缺乏其他致癌物代谢酶如微粒体环氧化物水解酶（mEH）和醌氧化物还原酶（NQO 1）表达的小鼠。 对CYP 1B 1缺失小鼠的研究表明，P450是多环芳烃致癌作用所必需的。缺乏mEH的小鼠也对致癌物敏感，因此表明致癌物活化的经典二醇-环氧化物途径是体内最重要的致癌作用。 为了产生可以更准确地用于预测人类药物和致癌物代谢的小鼠模型，正在使用细菌人工染色体制备P450人源化小鼠。携带人基因的转基因小鼠将与P450空小鼠繁殖以产生人源化小鼠。已生产出表达人CYP 2D 6的小鼠，其他小鼠正在制备中。

In mammals, a large number of enzymes exist that metabolize drugs and other xenobiotics. Cytochrome P450s are among the most important of these enzymes that are involved in metabolism of most therapeutically-used drugs. In addition, P450s catalyze the metabolic-activation of chemical carcinogens. The P450s involved in xenobiotic metabolism are found in the CYP1, CYP2 and CYP3 families. Each of these families consist of two or more subfamilies. The fact that P450s can metabolically-activate toxins and procarcinogens in vitro implies that they are involved in toxicity and cancer. However, it is not known whether P450s are required for the toxicity and carcinogenicity of chemicals in an intact animal. The only experiments suggestive of a role for P450s in cancer etiology are indirect chemically-induced transformation assays in cell culture, and genetic experiments in mice involving the Ah locus. No direct evidence is available to establish that P450s are necessary for carcinogenesis in an intact animal model system. To assess the potential contribution of P450s to acute chemical toxicity and the process of chemical carcinogenesis, and to determine their roles, if any, in mammalian development and physiological homeostasis, P450-null mice were produced. Mice lacking expression of other carcinogen metabolizing enzymes like the microsomal epoxide hydrolase (mEH) and the quinone oxidoeductase (NQO1) were also made. Studies with CYP1B1-null mice have revealed that this P450 is required for the carcinogenic efforts of polycyclic aromatic hydrocarbons. Mice lacking mEH are also sensitive to the carcinogens thus indicating that the classic diol-epoxide route of carcinogen activation is the most important or carcinogenesis in vivo. In order to produce mouse models that can more accurately be used to predict human drug and carcinogen metabolism, P450-humanized mice are being prepared using bacterial artificial chromosomes. Transgenic mice carrying the human genes will be bred with P450 null-mice to produce humanized mice. Mice expressing human CYP2D6 have been produced and others are under preparation.