Weber_1990_Birth.Defects.Orig.Artic.Ser_26_43

The human acetylation polymorphism has been known for more than three decades since its discovery during the metabolic investigation of the antituberculous hydrazine drug, isoniazid. The trait was originally known as the "isoniazid acetylation polymorphism" but is now usually abbreviated to the "acetylation polymorphism" because the acetylation of numerous hydrazine and arylamine drugs and other chemicals are subject to this trait. A. Individuals phenotype as "slow" acetylators, homozygous for the slow acetylator gene, or "rapid" acetylators either heterozygous or homozygous for the rapid acetylator gene. Differences in individual acetylating capacity are ascribed to differences in the activities of the arylamine acetylating enzymes (isozymic N-acetyltransferase variants) of the liver, intestinal mucosa and certain other tissues. The chromosomal locus of the human gene has not been determined, but linkage analysis in mice indicates that the N-acetyltransferase gene is closely linked to Esterase-1 on mouse chromosome 8. Recommendation: 1) That the chromosomal locus of the human acetylator gene(s) be determined. B. The acetylator phenotype is a lifelong, stable characteristic of the individual that can be determined by procedures using any of several test agents (eg, caffeine, isoniazid, sulfamethazine, sulfapyridine). All suitable test agents discriminate rapid and slow acetylator phenotypes, whereas caffeine enables homozygous and heterozygous rapid acetylators to be discriminated from each other and from slow acetylators. These procedures can be used with confidence to determine the acetylator status of healthy adults and children but caution is necessary in interpreting this information for infants, in altered physiologic states and in the presence of certain diseases and environmental substances. Recommendations: 1) That investigators should strongly consider the use of the caffeine test for acetylator phenotype determination in human epidemiologic studies of acetylation because of its advantages over other test agents that are available. 2) That efforts to determine the structure of the acetylator genes responsible for the human acetylator polymorphism, and to determine the genes responsible for the hereditary acetylator polymorphisms in animal models for the human trait be continued apace with efforts on the human system. 3) That an improved test to determine the acetylator status utilizing that information and current molecular biology approaches and techniques applied to tissues that are readily available in human subjects (eg, leukocytes) be developed at a high priority. C. The hereditary acetylator status of individuals provides valuable information about their therapeutic, pharmacologic and toxicologic responses and is a prognosticator of unusual susceptibility to toxicity from drugs widely used for the treatment of diverse diseases.