Hein D W, Rustan T D, Bucher K D, Martin W J, Furman E J
Department of Pharmacology, University of North Dakota School of Medicine, Grand Forks 58203.
Drug Metab Dispos. 1991 Sep-Oct;19(5):933-7.
Although mouse, hamster, and rabbit models of the human N-acetylation polymorphism have been identified and characterized, many investigations of arylamine toxicity and carcinogenicity are carried out in the rat, particularly the Fischer 344 (F-344) inbred rat. We partially characterized a new rat model of the N-acetylation polymorphism by determining expression of arylamine N-acetyltransferase activities in liver cytosols derived from adult male inbred F-344, WKY, and their F1 hybrid rat strains. Levels of N-acetyltransferase activity differed significantly between the strains for many arylamine substrates, with highest levels in F-344, lowest levels in WKY, and intermediate levels in F1 hybrids of these two parental strains. However, for some other arylamine substrates, levels of N-acetyltransferase activity did not differ significantly between the rat strains. Partial purification of rat liver cytosols from the three strains resulted in identification of two N-acetyltransferase isozymes. The levels of N-acetyltransferase activity of one isozyme differed significantly between strains analogous to the pattern observed in crude cytosol. In contrast, the levels of N-acetyltransferase activity of the second isozyme did not differ between the strains. Based upon these results, the F-344 inbred strain is designated a rapid acetylator phenotype, the WKY inbred strain is designated a slow acetylator phenotype, and F1 hybrids of the two parental strains are designated intermediate acetylator phenotype. The identification of acetylator phenotype-dependent and -independent hepatic N-acetyltransferase isozymes in the inbred rat mimics the biochemical basis for acetylator phenotype-dependent and -independent expressions of N-acetylation in humans and other mammalian species.
虽然人类N - 乙酰化多态性的小鼠、仓鼠和兔模型已被鉴定和表征，但许多关于芳胺毒性和致癌性的研究是在大鼠中进行的，尤其是费希尔344（F - 344）近交系大鼠。我们通过测定成年雄性近交F - 344、WKY及其F1杂交大鼠品系肝脏胞质溶胶中芳胺N - 乙酰转移酶活性的表达，对一种新的大鼠N - 乙酰化多态性模型进行了部分表征。对于许多芳胺底物，各品系间N - 乙酰转移酶活性水平存在显著差异，F - 344中活性水平最高，WKY中最低，这两个亲本品系的F1杂种中活性水平处于中间。然而，对于其他一些芳胺底物，大鼠品系间N - 乙酰转移酶活性水平无显著差异。对这三个品系的大鼠肝脏胞质溶胶进行部分纯化后，鉴定出两种N - 乙酰转移酶同工酶。一种同工酶的N - 乙酰转移酶活性水平在品系间差异显著，类似于在粗胞质溶胶中观察到的模式。相比之下，第二种同工酶的N - 乙酰转移酶活性水平在品系间无差异。基于这些结果，F - 344近交系被指定为快速乙酰化表型，WKY近交系被指定为慢速乙酰化表型，两个亲本品系的F1杂种被指定为中间乙酰化表型。在近交大鼠中鉴定出依赖和不依赖乙酰化表型的肝脏N - 乙酰转移酶同工酶，模拟了人类和其他哺乳动物物种中N - 乙酰化依赖和不依赖乙酰化表型表达的生化基础。
