Human arylamine N-
acetyltransferases (CoASAc;
NAT, EC 2.3.1.5) NAT1 and NAT2 play a key role in the metabolism of drugs and environmental chemicals and in the metabolic activation and detoxification of procarcinogens. Phenotyping analyses have revealed an association between
NAT enzyme activities and the risk of developing several forms of
cancer. As genotyping procedures have become available for NAT1 and NAT2 gene variations, hundreds of association studies on
NAT polymorphisms and
cancer risk have been conducted. Here we review the findings obtained from these studies. Evidence for a putative association of NAT1 polymorphism and myeloma, lung and
bladder cancer, as well as association of NAT2 polymorphisms with
non-Hodgkin lymphoma, liver, colorectal and
bladder cancer have been reported. In contrast, no consistent evidence for a relevant association of
NAT polymorphisms with brain, head & neck, breast, gastric, pancreatic or
prostate cancer have been described. Although preliminary data are available, further well-powered studies are required to fully elucidate the role of NAT1 in most human
cancers, and that of NAT2 in
astrocytoma,
meningioma, esophageal, renal, cervical and
testicular cancers, as well as in leukaemia and myeloma. This review discusses controversial findings on
cancer risk and putative causes of heterogeneity in the proposed associations, and it identifies topics that require further investigation, particularly mechanisms underlying association of
NAT polymorphisms and risk for subsets of
cancer patients with specific exposures, putative epistatic contribution of polymorphism for other
xenobiotic-metabolising
enzymes such as
glutathione S-
transferases of
Cytochrome P450 enzymes, and genetic plus environmental interaction.