Acetylator phenotype-dependent and -independent expression of arylamine N-acetyltransferase isozymes in rapid and slow acetylator inbred rat liver.
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.
Hein
D W
DW
Department of Pharmacology, University of North Dakota School of Medicine, Grand Forks 58203.
Rustan
T D
TD
Bucher
K D
KD
Martin
W J
WJ
Furman
E J
EJ
D000107:Acetylation; D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000096:biosynthesis / Q000235:genetics*; D003600:Cytosol / Q000201:enzymology; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics*; D008099:Liver / Q000201:enzymology*; D008297:Male; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics*; D051381:Rats; D011916:Rats, Inbred F344; D011921:Rats, Inbred WKY; D013997:Time Factors
D007527:Isoenzymes; D001191:Arylamine N-Acetyltransferase