METABOLIC PROCESSING AND DNA ADDUCTION OF HETEROCYCLIC AMINE FOOD MUTAGENS

我们对杂环化合物的代谢和DNA加合的研究 胺（HA）已经表明，这些化合物是前致癌物， 需要代谢活化来检测遗传毒性。 这些化合物， 在肉类的烹饪过程中，是诱变剂在艾姆斯 通过细胞色素P450代谢活化后的saltamine测定。 已经进行了三种HA的致癌性和代谢研究 在食蟹猴中。 我们发现2-氨基-3-甲基-咪唑[4，5-b] f]喹啉（IQ）是食蟹猴中的一种强效肝癌原。 我们 确定细胞色素P450介导的N- 羟基化和II相酯化是HA关键特征 在非人类灵长类动物中致癌。 第二阶段的四个途径已经 显示有助于IQ的N-羟胺的活化，2- 氨基-3，8-二甲基咪唑并[4，5-f]-喹喔啉（MeIQx）和2-氨基-1- 甲基-6-苯基咪唑并[4，5-B]-吡啶（PhIP）：O-乙酰基转移酶， 磺基转移酶、t-RNA合成酶和磷酸化酶。 主要的DNA IQ、MeIQx和PhIP的加合物已被鉴定为各自的C8- 鸟嘌呤加合物，表明DNA中这些化合物之间的相似性 形成加合物。 PhIP研究表明，食蟹猴具有 在体内代谢活化该化合物的良好能力， 这种激活导致DNA加合， 包括白色血细胞。 从这些新陈代谢中 研究，我们预测PhIP将对非人类灵长类动物致癌。 相比之下，食蟹猴中MeIQx的代谢活化较低 与缺乏致瘤性或较长的潜伏期相关 阶段（研究正在进行中）。 我们已经研究了代谢的HA在 大鼠乳腺，并确定O-乙酰转移酶是 乳腺组织中的主要II相酶。 PhIP代谢产物 母乳已被确认。 各种乳腺癌的作用 目前正在评估代谢物在乳腺癌发生中的作用。

Our studies on the metabolism and DNA adduction of the heterocyclic amines (HAs) have shown that these compounds are procarcinogens that require metabolic activation for genotoxicity. These compounds, produced in meats during the process of cooking, are mutagens in the Ames salmonella assay upon metabolic activation by cytochrome P450. Carcinogenicity and metabolism studies of three HAs have been undertaken in cynomolgus monkeys. We found that 2-amino-3-methyl-imidazo[4,5- f]quinoline (IQ) is a potent hepatocarcinogen in cynomolgus monkeys. We determined that metabolic processing by cytochrome P450-mediated N- hydroxylation and phase II esterification is a critical feature for HA carcinogenicity in nonhuman primates. Four phase II pathways have been shown to contribute to the activation of the 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): O-acetyltransferase, sulfotransferase, t-RNA synthetase, and phosphorylase. The major DNA adduct of IQ, MeIQx, and PhIP has been identified as the respective C8- guanine adduct, indicating a similarity among these compounds in DNA adducts formed. 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. From these metabolism studies, we predict that PhIP will be carcinogenic to nonhuman primates. In contrast, the metabolic activation of MeIQx is low in the cynomolgus monkeys and correlates with a lack of tumorigenicity or longer latency period (studies ongoing). We have examined the metabolism of HAs in the mammary gland of rats and determined that the O-acetyl-transferase is the principal phase II enzyme in the mammary tissue. PhIP metabolites in breast milk have been identified. The role that various mammary metabolites play in mammary carcinogenesis is currently being assessed.