METABOLIC PROCESSING AND DNA ADDUCTION OF HETEROCYCLIC ARYLAMINE FOOD MUTAGENS

杂环胺(HAA)包括一组在煮熟的食物中发现的化合物 蛋白质类食物，包括牛肉、鱼、鸡肉和猪肉。三个哈哈， 2-氨基-3-甲基咪唑[4，5-f]喹啉，2-氨基-3，8- 二甲基咪唑并[4，5-f]喹恶啉(MeIQx)和2-氨基-1-甲基-6- 苯基咪唑并[4，5-b]吡啶(PhIP)已被证明是有效的 Ames沙门氏菌致突变试验中的诱变剂和 啮齿动物模型。这些化合物的新陈代谢过程起着 在DNA加合物的形成中起着重要作用，DNA加合物是 致癌的启动。使用重组细胞色素P-450，我们 发现P-450IA2是主要的同工酶 HAs的N-羟基化，以及N-羟胺与DNA的反应 在体外，直接激活和进一步激活后通过 酯化反应。我们用大鼠肝脏进行的研究表明，第二阶段 N-羟胺的磺基转移酶和乙酰基代谢 转移酶进一步激活这些化合物。智商已经被证明是一种 非人灵长类动物中的肝脏致癌物质，而MeIQx和 PhIP正在进行中。智商和PhIP的DNA加合物都在 非人灵长类动物的组织。然而，MeIQx的加合物在 这些动物。N-羟基-N-葡萄糖醛酸基-IQ和N-羟基-N-葡萄糖醛酸基-PhIP 在喂食智商和PhIP的非人灵长类动物的尿液中发现， 分别表明这些化合物通过 N-羟基化在体内发生。我们发现，对于这三个人来说 化合物的解毒途径包括与 硫酸盐和葡萄糖醛酸苷。N-脱甲基化也是一种主要途径 对非人类灵长类动物的智商进行解毒。加上PhIP，4‘- 羟基化和硫酸盐化是一种主要的途径 解毒。作为体内研究的补充，第一阶段和第二阶段 IQ、MeIQx和PhIP的激活和解毒途径是 在体外检测靶标和非靶组织的分离组织部分 Ames沙门氏菌在非人灵长类和啮齿动物靶器官中的应用 致突变性测试、高效液相色谱和32-P-后标记分析。

Heterocyclic amines (HAA) comprise a group of compounds found in cooked proteinaceous foods, including beef, fish, chicken and pork. Three HAAs, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,8- dimethylimidazo[4,5-f]quinoxaline (MeIQx), and 2-amino-1-methyl-6- phenylimidazo[4,5-b]pyridine (PhIP), have been shown to be potent mutagens in the Ames Salmonella mutagenicity assay and carcinogens in rodent models. Metabolic processing of these compounds plays an important role in the formation of DNA adducts, a critical factor in the initiation of carcinogenesis. Using recombinant cytochrome P-450s, we found that P-450IA2 is the predominant isozyme responsible for the N-hydroxylation of HAAs, and that N-hydroxylamines are reactive with DNA in vitro, both directly and following further activation via esterification. Our studies using rat liver indicate that phase II metabolism of the N-hydroxylamines by sulfotransferase and acetyl- transferase further activate these compounds. IQ has been shown to be a liver carcinogen in the nonhuman primates, while studies with MeIQx and PhIP are ongoing. Both DNA adducts of IQ and PhIP have been found in tissues of nonhuman primates. Adducts of MeIQx, however, are very low in these animals. N-Hydroxy-N-glucuronyl-IQ and N-hydroxy-N-glucuronyl-PhIP have been found in the urine of nonhuman primates fed IQ and PhIP, respectively, indicating that activation of these compounds via N-hydroxylation occurs in vivo. We have found that for all three compounds the pathways for detoxification include conjugation with sulfate and glucuronides. N-Demethylation is also a predominant pathway for detoxification of IQ in nonhuman primates. With PhIP, 4'- hydroxylation followed by sulfation is a predominant pathway for detoxification. To supplement the in vivo studies, phase I and II pathways of activation and detoxification of IQ, MeIQx, and PhIP are being examined in vitro in isolated tissue fractions from target and non- target organs of nonhuman primates and rodents using Ames Salmonella mutagenicity testing, HPLC, and 32-P-postlabling analysis.