HUMAN ACETYLTRANSFERASE POLYMORPHISMS

Conjugation of primary amino and hydroxylamino groups with acetate, ca talyzed by acetyl CoA-dependent arylamine acetyltransferase (NAT) enzy mes, may play an important role in the intricate series of metabolic p athways that produce or prevent toxicity following exposure to home- a nd heterocyclic arylamine and hydrazine xenobiotics. Two independently regulated and kinetically distinct human acetyltransferases are now k nown to exist, namely NAT1 and NAT2. Interindividual variation in NAT2 function is associated with the classical isoniazid acetylation polym orphism which was discovered over forty years ago. At last count, fift een variant alleles at the NAT2 gene locus have been linked to the iso niazid 'acetylator phenotype', and each of these can be identified in population studies using specific PCR-based genotyping tests. On the o ther hand, NAT1 shows kinetic selectivity for compounds whose disposit ion is unrelated to the classical isoniazid acetylation polymorphism. NAT1 expression is also phenotypically variable in human populations, at least in part due to allelic differences at the NAT1 gene locus. Ni ne NAT1 variant alleles have been described to date, of which NAT114 and NAT115 clearly produce defective NAT1 proteins and lead to functi onal impairment in the metabolism of NAT1-selective substrates both in vivo and in vitro. On the other hand, it has been reported that the N AT110 variant associates with elevated NAT1 activity and increased ri sk for cancers of the bladder and colon. Because of the important toxi cologic consequences of allelic variation in NAT1 and NAT2 function fo r the metabolic activation of arylamine and heterocyclic amine procarc inogens, further studies are needed to improve our understanding of th e extent of NAT allelic variation, to determine the functional capacit y of each variant gene product, and to develop accurate methods of det ecting them in population and epidemiological studies.