METABOLIC PROCESSING AND DNA ADDUCTION OF HETEROCYCLIC ARYLAMINE FOOD MUTAGENS

食品中的杂环芳香胺（哈斯）主要存在于肉类中 在烹饪的过程中。 迄今为止，已确定了19个哈斯 （部分确定）在各种熟肉。 许多这些化合物 在艾姆斯沙门氏菌试验中是强效诱变剂， 在大鼠和/或小鼠中显示为致癌的。 我们还发现，2- 氨基-3-甲基咪唑并[4，5-f]喹啉（IQ）是一种强效肝癌原， 食蟹猴 我们的研究表明，这些化合物 需要代谢活化以产生遗传毒性的前致癌物。 因此，在本发明中， 这些化合物的代谢过程是一个关键特征， 关于致癌性。 审查第二阶段的研究 IQ、2-氨基-3，8-二甲基咪唑[4，5- f]喹喔啉（MeIQx）和2-氨基-1-甲基-6-苯基咪唑[4，5-B]吡啶 （PhIP）表明，四种途径可能有助于激活这些 化合物：O-乙酰基转移酶、磺基转移酶、t-RNA合成酶和 磷酸酶。 代谢量由组织决定， 物种和基质。 DNA的特性研究 哈斯的加合物表明，IQ、MeIQx和 PhIP与鸟嘌呤碱基形成三种主要加合物。 的主要加合物 这些化合物中的每一种都被合成并鉴定为C8-鸟嘌呤 加合物，表明这些化合物在DNA加合物中的相似性 形成了 在我们的P-后标记的配置文件中确定的主要加合物。 PhIP研究表明，食蟹猴具有良好的能力， 在体内代谢活化该化合物， 导致DNA加合，可以在所有检查的组织中发现， 包括白色血细胞。 激活的主要途径是 鉴定为N-羟基化。 解毒的主要途径是 鉴定为4 '-羟基化，然后与硫酸酯缀合。

The food-derived heterocyclic arylamines (HAAs) are produced in meats during the process of cooking. To date, 19 HAAs have been identified (partially identified) in various cooked meats. Many of these compounds are potent mutagens in the Ames Salmonella assay and 10 HAAs have been shown to be carcinogenic in rats and/or mice. We also showed that 2- amino-3-methylimidazo[4,5-f]quinoline (IQ) is a potent hepatocarcinogen in cynomolgus monkeys. Our studies have shown that these compounds are procarcinogens that require metabolic activation for genotoxicity. Thus, the metabolic processing of these compounds is a critical feature with respect to their carcinogenicity. Studies examining the phase II activation of N-hydroxylamines of IQ, 2-amino-3,8-dimethylimidazo[4,5- f]quinoxaline (MeIQx), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) showed that four pathways may contribute to the activation of these compounds: O-acetyltransferase, sulfotransferase, t-RNA synthetase, and phosphatase. The amount of metabolism was determined by the tissue, the species, and the substrate. Studies on the characterization of DNA adducts of HAAs showed that the N-acetoxy derivatives of IQ, MeIQx, and PhIP form three major adducts with the guanine base. The major adduct of each of these compounds was synthesized and identified as the C8-guanine adduct, indicating a similarity among these compounds in DNA adducts formed. The major adducts were identified in our P-postlabeling profiles. Studies with PhIP show that cynomolgus monkeys possess a good capacity to metabolically activate this compound in vivo and that this activation results in DNA adduction that can be found in all tissues examined to date, including white blood cells. The major pathway of activation was identified as N-hydroxylation. The major pathway of detoxification was identified as 4'-hydroxylation followed by conjugation with sulfate.