Extrahepatic expression of N-acetylator genotype in the inbred hamster.
The genetic control of S-acetylcoenzyme A (AcCoA)-dependent N-acetyltransferase activity (EC 2.3.1.5) was investigated in liver, intestine, kidney, and lung cytosols derived from homozygous rapid acetylator (Bio. 87.20), heterozygous acetylator (Bio. 87.20 X 82.73/H F1), and homozygous slow acetylator (Bio. 82.73/H) Syrian inbred hamsters. AcCoA-dependent N-acetyltransferase activity was highest in hepatic cytosol, followed by intestine, kidney, and lung cytosol. In each of these tissues, cytosolic N-acetyltransferase exhibited an acetylator genotype-dependent activity with highest levels in homozygous rapid, intermediate levels in heterozygous F1 progeny, and lowest levels in homozygous slow acetylators. The ratio of N-acetyltransferase activity between acetylator genotypes was in general substrate dependent but not tissue dependent. Acetylator genotype-dependent N-acetyltransferase activity differences were highest for p-aminobenzoic acid, followed by p-aminosalicylic acid, 2-aminofluorene, and beta-naphthylamine. Expression of isoniazid N-acetyltransferase activity in each tissue was acetylator genotype independent. Determination of Michaelis-Menten kinetic constants in each tissue suggested that p-aminobenzoic acid N-acetyltransferase activity was acetylator genotype-dependent because of catalysis by an isozyme(s) that is both an apparent Km and a Vmax variant. In contrast, the acetylator genotype-independent expression of isoniazid N-acetyltransferase activity in each tissue appeared to result from a common isozyme(s) present in each tissue with equivalent kinetic constants in the two phenotypes. These data suggest that acetylator genotype-dependent expression of AcCoA-dependent N-acetyltransferase activity in extrahepatic tissues may play an important role in hereditary predisposition to toxicity and/or carcinogenesis in extrahepatic organs following exposure to arylamine drugs and foreign chemicals.
D000107:Acetylation; D000123:Acetyltransferases / Q000235:genetics*; D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D006224:Cricetinae; D003600:Cytosol / Q000201:enzymology; D005786:Gene Expression Regulation; D005838:Genotype; D066298:In Vitro Techniques; D007422:Intestines / Q000201:enzymology; D007668:Kidney / Q000201:enzymology; D008099:Liver / Q000201:enzymology; D008168:Lung / Q000201:enzymology; D008647:Mesocricetus; D011110:Polymorphism, Genetic; D013379:Substrate Specificity
D000123:Acetyltransferases; D001191:Arylamine N-Acetyltransferase