Acetylation

Abstract

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. 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. 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. More recently, the acetylator status has been implicated as an important factor modulating individual susceptibility to chemically induced cancer. An extensive series of epidemiologic studies, particularly of persons occupationally exposed to arylamines, shows a statistically significant association between the slow acetylator phenotype and urinary bladder cancer. More limited information shows a significant association between the rapid acetylator status and colorectal cancer. Isolated studies suggest that the acetylator status may be implicated as a susceptibility factor in cancer of the pharynx, larynx and stomach. One additional study suggests that prolonged use of permanent arylamine hair dyes by older women may favor the development of breast cancer in this subset of breast cancer patients although the effect of the acetylator status on the outcome was not evaluated. D. Mechanistic studies of the metabolic activation of arylamine carcinogens and studies of nuclear DNA damage induced by arylamine carcinogens in intact animals, in tissues, and in cells isolated in culture from animal models expressing a hereditary acetylation polymorphism, including rapid and slow acetylator congenic inbred mouse strains, provide strong support for the human epidemiologic observations. Additionally, animal studies show that several metabolic steps in the metabolic activation of arylamines other than acetylation, including N-hydroxylation, sulfation, and deacetylation, are subject to appreciable genetic variation. E. The utility of DNA- and protein-arylamine carcinogen adducts as quantitative predictors of exposure and risk of arylamine-induced cancer in rapid and slow acetylators is unknown. However, several new and highly specific techniques of great sensitivity are available and investigations now in progress should aid in assessing this relationship.