Partial purification and properties of the isoniazid transacetylase in human liver. Its relationship to the acetylation of p-aminosalicylic acid.

The heritable trait of rapid and slow inactivation of isoniazid (isonicotinic acid hydrazide) in man is a topic of considerable interest in the developing field of pharmacogenetics (1). Although differences in acetylation appear to be the principal reason for inactivation differences, knowledge of the specific enzymic basis as well as of the relationship of this trait to the acetylation of chemically related compounds is scant. Some in vitro information has been obtained. Localization of the variability in acetylation to the transacetylase has been reported by two laboratories. Evans and White, using homogenate of wedge biopsies of human liver, successfully correlated isoniazid inactivation phenotype and the disappearance rate of either isoniazid or sulfamethazine [N'(4,6dimethyl-2pyrimidinyl) sulfanilamide] in the presence of both generated and fixed concentrations of acetyl-CoA (2, 3). A suggestive correlation was found with the rate of hydralazine (1-hydrazinophthalazine) disappearance as well. p-Aminobenzoic acid (PABA) and sulfanilamide were not metabolized. While using different methods, we reported in a preliminary communication that, in the presence of constant acetyl-CoA, wide variations in isoniazid acetylation activity were found in the soluble fraction of postmortem liver and intestinal mucosa (4). The activity could be concentrated by 50%o saturation with ammonium sulfate. Hydralazine was a very strong inhibitor of the reaction, but