Role of Xenobiotic Metabolism in Cancer Susceptibility

在哺乳动物中，存在大量的酶来代谢药物和其他的外源物。细胞色素p450是这些酶中最重要的酶之一，参与大多数治疗用药物的代谢。此外，p450还能催化化学致癌物的代谢活化。参与外源代谢的p450存在于CYP1、CYP2和CYP3家族中。这些科中的每一个都由两个或更多的亚科组成。p450可以在体外代谢激活毒素和致癌原，这一事实表明它们参与毒性和癌症。然而，尚不清楚p450是否需要用于化学物质在完整动物体内的毒性和致癌性。唯一提示p450在癌症病因学中起作用的实验是细胞培养中的间接化学诱导转化试验，以及涉及Ah位点的小鼠遗传实验。在完整的动物模型系统中，没有直接证据证明p450是致癌所必需的。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），我们制造了p450缺失小鼠。同时制备了其他致癌物代谢酶如微粒体环氧化物水解酶（mEH）和醌氧化酶（NQO1）缺乏表达的小鼠。

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.