Polymorphic NATs and cancer predisposition.
The acetylation polymorphism, discovered 40 years ago, holds a special place as one of the first described examples of a pharmacogenetic defect affecting xenobiotic biotransformation capacity in human populations. The genetically determined N-acetyltransferase activity is involved in activation/inactivation reactions of numerous xenobiotics. Therefore, it has been suggested that slow acetylator status may modify the individual responses to various chemicals. In humans, two genes, NAT1 and NAT2, are responsible for N-acetyltransferase activity. To date several allelic variants of both NAT1 and NAT2 have been detected, and it has been suggested that some of them modify individual susceptibility to cancer. Slow NAT2 acetylation capacity has been suggested as conferring increased risk of bladder, breast, liver and lung cancers, and decreased risk of colon cancer, whereas a prominent change in the NAT1 gene, putatively associated with increased NAT1 activity, has been suggested as increasing the risk of bladder and colon cancer and decreasing that of lung cancer. While three of the NAT2 variants have been shown to account for most of the slow NAT2 acetylator genotypes in Caucasians, less complete data are available on how the NAT1 variants modify NAT1 activity in vivo. This review discusses present knowledge on NAT polymorphisms, particularly in relation to individual cancer predisposition.
Hirvonen
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Finnish Institute of Occupational Health, Department of Industrial Hygiene and Toxicology, Helsinki.
D000107:Acetylation / Q000187:drug effects; D000483:Alleles; D001191:Arylamine N-Acetyltransferase / Q000145:classification / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D001711:Biotransformation; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation; D005828:Genetics, Population; D005838:Genotype; D006801:Humans; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics*; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics*
D001191:Arylamine N-Acetyltransferase