Abstract
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.
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|