Thorgeirsson S S, Davis C D, Schut H A, Adamson R H, Snyderwine E G
Laboratory of Experimental Carcinogenesis, National Cancer Institute, Bethesda, Maryland 20892, USA.
Princess Takamatsu Symp. 1995;23:85-92.
During the past decade and a half, a number of potent mutagens belonging to the class of heterocyclic aromatic amines (HCA) have been isolated and identified from cooked fish, beef, fowl and other meat, and from beef extracts. Several of these HCA mutagens have also been found to be carcinogenic in rodent bioassays, and one of these compounds, 2-amino-3-methylimidazo-[4,5-f]-quinoline (IQ), has recently been found to cause hepatocellular carcinoma in cynomolgus monkeys. The potential etiological role of these mutagens and carcinogens in human cancer prompted us to evaluate the genotoxicity of these compounds in both nonhuman primates and rodents, with particular emphasis on the formation and tissue distribution of DNA adducts. We selected three compounds for this study based on several factors including chemical structure, mutagenic activity in vitro, concentration in cooked food, and carcinogenic activity in the rodent test system. These were IQ, 2-amino-3,8-dimethylimidazo[4,5-f]-quinoxaline (8-MeIQx), and 2-amino-1-methyl-6-phenylimidazo-[4,5-b]-pyridine (PhIP). To maximize the sensitivity of the DNA adduct measurements, we have employed the 32P-postlabeling method to analyze levels and tissue distribution of DNA adducts derived from IQ 8-MeIQx, and PhIP. We have measured DNA adduct formation for all three compounds in various tissues and white blood cells of monkeys following both acute and chronic administration. Both IQ and PhIP form high levels of adducts in a number of organs, particularly liver, kidney, and heart. In contrast, administration of 8-MeIQx to the cynomolgus monkeys results in the formation of only low adduct levels with many tissues showing no detectable levels of adducts. Studies in rodents have also shown that IQ and PhIP from DNA adducts in a number of organs in addition to those that are targets for carcinogenic effects of these agents. Although high DNA adduct levels of HCA are generally found in target organs for HCA induced carcinogenesis the widespread distribution of the adducts in organs not associated with the carcinogenic effects suggest that HCA exposure may be a possible etiological factor in cardiovascular diseases and other degenerative ailments.
在过去十五年间，已从熟鱼、牛肉、禽肉及其他肉类以及牛肉提取物中分离并鉴定出多种属于杂环芳香胺（HCA）类的强效诱变剂。其中几种HCA诱变剂在啮齿动物生物测定中也被发现具有致癌性，最近还发现这些化合物之一，即2-氨基-3-甲基咪唑-[4,5-f]-喹啉（IQ），可在食蟹猴中引发肝细胞癌。这些诱变剂和致癌物在人类癌症中潜在的病因学作用促使我们评估这些化合物在非人类灵长类动物和啮齿动物中的遗传毒性，尤其着重于DNA加合物的形成及组织分布。基于化学结构、体外诱变活性、熟食中的浓度以及啮齿动物测试系统中的致癌活性等多个因素，我们选择了三种化合物进行此项研究。它们分别是IQ、2-氨基-3,8-二甲基咪唑[4,5-f]-喹喔啉（8-MeIQx）以及2-氨基-1-甲基-6-苯基咪唑-[4,5-b]-吡啶（PhIP）。为了最大限度地提高DNA加合物测量的灵敏度，我们采用了32P后标记法来分析源自IQ、8-MeIQx和PhIP的DNA加合物的水平及组织分布。我们在急性和慢性给药后，测量了猴子各种组织和白细胞中这三种化合物的DNA加合物形成情况。IQ和PhIP在许多器官中都形成了高水平的加合物，尤其是肝脏、肾脏和心脏。相比之下，给食蟹猴施用8-MeIQx仅导致形成低水平的加合物，许多组织中未检测到加合物水平。对啮齿动物的研究还表明，IQ和PhIP除了在这些物质致癌作用的靶器官外，还在许多器官中形成DNA加合物。尽管HCA的高DNA加合物水平通常在HCA诱导致癌作用的靶器官中被发现，但加合物在与致癌作用无关的器官中的广泛分布表明，HCA暴露可能是心血管疾病和其他退行性疾病的一个可能病因。
