Talalay P, Prochaska H J, Spencer S R
Department of Pharmacology and Molecular Sciences, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205.
Princess Takamatsu Symp. 1990;21:177-87.
Most chemical carcinogens require activation to reactive electrophilic forms by Phase 1 enzymes (cytochromes P-450) in order to exert their toxic and neoplastic effects. The resultant electrophiles are susceptible to metabolic conjugation and other types of detoxications by Phase 2 enzymes (glutathione transferases, NAD(P)H: quinone reductase, glucuronosyltransferases). The balance between Phase 1 and Phase 2 enzymes is an important determinant of whether exposure to carcinogens will result in toxicity and neoplasia. Measurements of the activity of quinone reductase (QR) provide an efficient method for studying the potency and mechanism of Phase 2 enzyme induction. QR can be measured easily in murine hepatoma cells (Hepa lclc7) grown in microtiter plate wells, and the inductive response of these cells closely parallels the behavior of rodent tissues in vivo. Some inducers (such as large planar aromatics) are bifunctional; they induce both Phase 1 and Phase 2 enzymes and require binding to the Ah receptor and enhanced transcription of the cytochrome P1-450 system. Other inducers (e.g., phenolic antioxidants, 1, 2-dithiole-3-thiones, coumarins, thiocarbamates) are monofunctional and are independent of Ah receptor function. Monofunctional enzyme induction protects against carcinogens. The induction of Phase 2 enzymes by monofunctional inducers depends on the presence, or acquisition by metabolism, of electrophilic centers, and many of these inducers are Michael reaction acceptors. Our search for chemoprotective enzyme inducers for potential use as chemoprotectors in man is currently focused on fumarate derivatives, as well as on the identification of other monofunctional inducers in extracts of vegetables.
大多数化学致癌物需要通过Ⅰ相酶（细胞色素P - 450）激活成为具有反应活性的亲电形式，才能发挥其毒性和致瘤作用。生成的亲电物质易被Ⅱ相酶（谷胱甘肽转移酶、NAD(P)H：醌还原酶、葡萄糖醛酸转移酶）进行代谢结合及其他类型的解毒作用。Ⅰ相酶和Ⅱ相酶之间的平衡是接触致癌物是否会导致毒性和肿瘤形成的一个重要决定因素。醌还原酶（QR）活性的测定为研究Ⅱ相酶诱导的效力和机制提供了一种有效的方法。在微量滴定板孔中生长的小鼠肝癌细胞（Hepa lclc7）中可以很容易地测量QR，并且这些细胞的诱导反应与啮齿动物组织在体内的行为密切相似。一些诱导剂（如大的平面芳烃）具有双功能；它们既诱导Ⅰ相酶也诱导Ⅱ相酶，并且需要与芳烃受体结合并增强细胞色素P1 - 450系统的转录。其他诱导剂（例如酚类抗氧化剂、1,2 - 二硫杂环戊烯 - 3 - 硫酮、香豆素、硫代氨基甲酸盐）是单功能的，并且独立于芳烃受体功能。单功能酶诱导可预防致癌物。单功能诱导剂对Ⅱ相酶的诱导取决于亲电中心的存在或通过代谢获得，并且这些诱导剂中的许多是迈克尔反应受体。我们目前正在寻找有可能用作人体化学保护剂的化学保护酶诱导剂，重点是富马酸盐衍生物，以及鉴定蔬菜提取物中的其他单功能诱导剂。
