Hein D W, Rustan T D, Ferguson R J, Doll M A, Gray K
Department of Pharmacology and Toxicology, University of North Dakota School of Medicine, Grand Forks 58202-9037.
Arch Toxicol. 1994;68(2):129-33. doi: 10.1007/s002040050045.
Recombinant human NAT1 and polymorphic NAT2 wild-type and mutant N-acetyltransferases (encoded by NAT2 alleles with mutations at 282/857, 191, 282/590, 341/803, 341/481/803, and 341/481) were expressed in Escherichia coli strains XA90 and/or JM105, and tested for their capacity to catalyze the metabolic activation (via O-acetylation) of the N-hydroxy (N-OH) derivatives of 2-aminofluorene (AF), and the heterocyclic arylamine mutagens 2-amino-3-methylimidazo [4,5-f]quinoline (IQ), 2-amino-3,4-dimethyl-imidazo[4,5-f]quinoxaline (MeIQx), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Both NAT1 and NAT2 (including all mutant human NAT2s tested) catalyzed the metabolic activation of each of the N-hydroxyarylamines to products that bound to DNA. Metabolic activation of N-OH-AF was greater than that of the heterocyclic N-hydroxyarylamines. The relative capacity of NAT1 versus NAT2 to catalyze activation varied with N-hydroxyarylamine substrate. N-OH-MeIQx and N-OH-PhIP exhibited a relative specificity for NAT2. These results provide mechanistic support for a role of the genetic acetylation polymorphism in the metabolic activation of heterocyclic amine mutagens and carcinogens.
重组人NAT1以及多态性NAT2野生型和突变型N - 乙酰基转移酶（由NAT2等位基因编码，在282/857、191、282/590、341/803、341/481/803和341/481处有突变）在大肠杆菌菌株XA90和/或JM105中表达，并测试它们催化2 - 氨基芴（AF）的N - 羟基（N - OH）衍生物以及杂环芳胺诱变剂2 - 氨基 - 3 - 甲基咪唑[4,5 - f]喹啉（IQ）、2 - 氨基 - 3,4 - 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）的代谢活化（通过O - 乙酰化）的能力。NAT1和NAT2（包括所有测试的突变型人NAT2）都催化每种N - 羟基芳胺代谢活化为与DNA结合的产物。N - OH - AF的代谢活化大于杂环N - 羟基芳胺。NAT1与NAT2催化活化的相对能力随N - 羟基芳胺底物而变化。N - OH - MeIQx和N - OH - PhIP对NAT2表现出相对特异性。这些结果为遗传乙酰化多态性在杂环胺诱变剂和致癌物代谢活化中的作用提供了机制支持。
