N-acetylation pharmacogenetics. Michaelis-Menten constants for arylamine drugs as predictors of their N-acetylation rates in vivo.
Michaelis-Menten constants for two in vivo monomorphically N-acetylated substrates, p-aminobenzoic acid and p-aminosalicylic acid, and two in vivo polymorphically N-acetylated substrates, sulfamethazine and procainamide, were determined with an improved assay procedure using liver N-acetyltransferase from rapid and slow acetylator rabbit. The slow rabbit liver isozyme proves to be a Vmax and a Km variant for p-aminobenzoic acid and p-aminosalicylic acid. Mean differences in the apparent Vmax for rapid acetylators were 39-fold greater for p-aminobenzoic acid and 16-fold greater for p-aminosalicylic acid. The apparent Km values for the slow acetylator enzyme were lower than 5 microM, whereas the apparent Km values for the rapid acetylator phenotype were at least 15 times higher, with a value of 105 +/- 21 microM for p-aminobenzoic acid and 74 +/- 16 microM for p-aminosalicylic acid. In contrast, for the polymorphic substrates, sulfamethazine and procainamide, rapid rabbit liver N-acetyltransferase was only a Vmax variant with a mean specific activity that was 13-fold higher than that for slow acetylator.
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D010129:4-Aminobenzoic Acid / Q000378:metabolism*; D000105:Acetyl Coenzyme A / Q000378:metabolism; D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D062365:Aminobenzoates / Q000378:metabolism*; D010131:Aminosalicylic Acid / Q000378:metabolism*; D000636:Aminosalicylic Acids / Q000378:metabolism*; D000818:Animals; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D011342:Procainamide / Q000378:metabolism*; D011817:Rabbits; D013418:Sulfamethazine / Q000378:metabolism*
D062365:Aminobenzoates; D000636:Aminosalicylic Acids; D013418:Sulfamethazine; D010131:Aminosalicylic Acid; D000105:Acetyl Coenzyme A; D000123:Acetyltransferases; D011342:Procainamide; D010129:4-Aminobenzoic Acid