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

Abstract

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'-(4,6-dimethyl-2-pyrimidinyl) 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

Acetylator status and diabetic neuropathy

“…The rate of activity of this enzyme is genetically determined and populations may be divided into 'slow' and 'fast' acetylators with implications for the dosage requirements of a variety of drugs [2]. The total N-acetyltransferase activity present in the liver of a rapid acetylator is at least twice as high as that found in a slow acetylator [3] and there is considerable racial variation with most Caucasoid populations having approximately 50% of their number in each group [2]. Slow acetylators are more prone than fast acetylators to develop peripheral neuropathy when treated with isoniazid [4,5] and a study from Finland found that seven out of nine Type I (insulin-dependent) diabetic children were fast acetylators [6].…”

Pharmacogenetics of the Human Arylamine N-Acetyltransferases

“…In 1965, Jenne [24] suggested that acetylation of monomorphic and polymorphic substrates was mediated by separate enzymes, a prediction confirmed almost 25 years later when the cloning of the human NAT1 and NAT2 genes was achieved [25] and functional characterization of their expressed products and those present in human liver was studied [26]. It is now clear that human NAT1 and NAT2 are independently expressed proteins and that NAT2 possesses catalytic specificity for those substrates whose rates of acetylation show polymorphic variation correlating with that of isoniazid [26,27].…”

Polymorphism of Human Acetyltransferases

“…These substrates are called monomorphic, in contrast to the polymorphic substrates isoniazid, procainamide, and others. Jenne et al (9), during the first detailed biochemical studies of drug acetylation in man, proposed that two different N-acetyltransferase enzymes were responsible for the metabolism of monomorphic and polymorphic arylamines. Moreover, it appeared that the observed genetic variation in acetylation of polymorphic substrates was related to differences in the quantity of one of these enzymes present in human liver cytosol, rather than to altered kinetic characteristics of a structural variant.…”