Hein D W, Rustan T D, Doll M A, Bucher K D, Ferguson R J, Feng Y, Furman E J, Gray K
Department of Pharmacology and Toxicology, University of North Dakota School of Medicine, Grand Forks 58203.
Toxicol Lett. 1992 Dec;64-65 Spec No:123-30. doi: 10.1016/0378-4274(92)90181-i.
Arylamine chemicals inflict a number of toxicities including cancer. Metabolic activation (i.e., oxidation) is required in order to elicit the toxic actions. Acetylation is an important step in the metabolic activation and deactivation of arylamines. N-acetylation forms the amide derivative which is often nontoxic. However, O-acetylation of the N-hydroxyarylamine (following oxidation) yields an acetoxy arylamine derivative which breaks down spontaneously to a highly reactive arylnitrenium ion, the ultimate metabolite responsible for mutagenic and carcinogenic lesions. Human capacity to acetylate arylamine chemicals is subject to a genetic polymorphism. Individuals segregate into rapid, intermediate, or slow acetylator phenotypes by Mendelian inheritance regulated by a single gene encoding for a polymorphic acetyltransferase isozyme (NAT2). Individuals homozygous for mutant alleles are deficient in the polymorphic acetyltransferase and are slow acetylators. A second acetyltransferase isozyme (NAT1) is monomorphic and is not regulated by the acetylator genotype. Several human epidemiological studies suggest an association between slow acetylator phenotype and urinary bladder cancer. In contrast, a few studies suggest a relationship between rapid acetylator phenotype and colorectal cancer. The basis for this paradox may relate to the relative importance of N- versus O-acetylation in the etiology of these cancers. Conclusions drawn from human epidemiological data are often compromised by uncontrolled environmental and other genetic factors. Our laboratory recently completed construction of homozygous rapid, heterozygous intermediate, and homozygous slow acetylator congenic Syrian hamsters to be homologous in greater than 99.975% of their genomes. The availability of these acetylator congenic lines should eliminate genetic variability in virtually all aspects of arylamine carcinogenesis except at the acetylator gene locus. Ongoing studies in these congenic hamster lines should provide unequivocal information regarding the role of genetic acetylator phenotype in susceptibility to arylamine-related cancers.
芳胺类化学物质会引发多种毒性，包括致癌性。为了引发毒性作用，需要进行代谢活化（即氧化）。乙酰化是芳胺代谢活化和失活的重要步骤。N-乙酰化形成酰胺衍生物，通常无毒。然而，N-羟基芳胺（氧化后）的O-乙酰化会产生乙酰氧基芳胺衍生物，该衍生物会自发分解为高反应性的芳基氮鎓离子，这是导致诱变和致癌损伤的最终代谢产物。人类对芳胺类化学物质进行乙酰化的能力存在遗传多态性。个体通过由编码多态性乙酰转移酶同工酶（NAT2）的单个基因调控的孟德尔遗传，分为快速、中间或慢速乙酰化表型。纯合突变等位基因的个体缺乏多态性乙酰转移酶，是慢速乙酰化者。第二种乙酰转移酶同工酶（NAT1）是单态的，不受乙酰化者基因型的调控。多项人类流行病学研究表明，慢速乙酰化表型与膀胱癌之间存在关联。相比之下，一些研究表明快速乙酰化表型与结直肠癌之间存在关系。这种矛盾的基础可能与N-乙酰化和O-乙酰化在这些癌症病因中的相对重要性有关。从人类流行病学数据得出的结论往往受到不受控制的环境和其他遗传因素的影响。我们实验室最近完成了纯合快速、杂合中间和纯合慢速乙酰化近交叙利亚仓鼠的构建，它们在超过99.975%的基因组中是同源的。这些乙酰化近交系的可用性应该可以消除芳胺致癌作用几乎所有方面的遗传变异性，除了乙酰化基因位点。对这些近交仓鼠系正在进行的研究应该会提供关于遗传乙酰化表型在对芳胺相关癌症易感性中的作用的明确信息。
