8p22

AAC2,NAT-2,PNAT

Determination of the NAT2 genotype or phenotype has been proposed to predict adverse reactions in patients with tuberculosis receiving isoniazid, prior to the concomitant administration of drug combinations such as procainamide-phenytoin or doxycyline-rifampin. In addition, several human diseases have been related to NAT2 polymorphism. There are described below.

Brain cancer

Preliminary findings argue for association of a trend towards higher risk in individuals classified as NAT2 homozygous rapid acetylators in patients with astrocytoma or meningioma.

Lung cancer

Several studies based on an initial hypothesis that slow acetylation may increase the risk of developing lung cancer have been conducted. This hypothesis has been reinforced by studies indicating that slow acetylation, especially if it is associated to defect genotypes for other phase II enzymes, may confer increased susceptibility to the formation of adducts. Several studies have concluded that the NAT2 slow acetylation genotype causes a marginally increased risk of developing lung cancer. In spite of these findings, present evidence suggests that the NAT2 polymorphism alone does not constitute a relevant risk factor for lung cancer. However this polymorphism may reinforce the effect of other genetic and/or environmental factors.

Liver cancer

A role for xenobiotic-metabolising enzymes in liver carcinogenesis is to be expected among patients with environmentally-related liver cancer since, besides viral hepatitis, liver cancer may be related to environmental substances. The findings obtained in patients with primary liver cancer not related to viral hepatitis are consistent and indicate a minor, but relevant, association of the slow NAT2 acetylation status and predisposition to liver cancer.

Colorectal cancer

The hypothesis that acetylator status may predispose to a determined cancer risk is based on a differential effect of N-acetylation as a potential detoxification step and O-acetylation as a potential carcinogen-activation step. In the case of colorectal cancer it was hypothesized that O-acetylation is more relevant that N-acetylation, and therefore the rapid acetylation genotype is the putative risk status associated with colorectal cancer. Sufficient evidence is available to rule out a relevant association of NAT genotypes alone with colorectal cancer risk. However, the putative interaction of meat consumption and the NAT2 genotype deserves particular attention.

Bladder cancer

Despite the large number of studies and meta-analyses performed in several human populations, current evidence is not sufficient to confirm unambiguously an association of NAT2 polymorphism to overall bladder cancer risk. A general association of the slow acetylation status with bladder cancer risk has not been fully confirmed, although meta-analyses have obtained positive findings for a modest association of the slow NAT2 acetylation genotype with bladder cancer risk, with odds ratio values between 1.3 and 1.5. Furthermore, the biological basis for the putative association is uncertain. In diverse independent studies, mutagenicity in urine was tested in individuals exposed to urban pollution, smoking, red meat intake or textile dyes. In all cases, no higher mutagenicity in slow NAT2 acetylators could be established when compared to these or rapid acetylators, and in fact among individuals exposed to urban pollution, rapid acetylators showed a higher mutagenicity in urine than slow acetylators. In a study investigating the influence of NAT genotypes in the association between permanent hair dyes and bladder cancer, a significant association of the slow NAT2 acetylation genotype was identified. However these findings could not be replicated in other studies.

Breast cancer

After dozens of studies involving several thousands of breast cancer patients, as well as meta-analyses, today it is obvious that no major association of NAT2 polymorphism and breast cancer risk exists.

Head and neck cancer

Since chemical compounds present in tobacco are inactivated by phase II enzymes, it has been proposed that head and neck cancer risk could be modified by NAT genotypes. However, overall findings indicate that no relevant association between NAT2 polymorphism and head and neck cancer risk is to be expected.

Other diseases

Although a relation of risk may be definitely discarded for systemic lupus erythematosus (SLE), inflammatory bowel disease and endometriosis, more research is needed for rheumatoid arthritis, Parkinsons, Alzheimers, Behçets and periodontal diseases, as current results are inconclusive but suggest a possible relation with NAT2 polymorphism. In diabetes mellitus the possible relation with the rapid phenotype may be due to acquired metabolic changes and more genotyping studies are needed. NAT2 slow metabolizers are more prone to the side effects of polymorphically acetylated drugs, as is the SLE-like syndrome induced by hydralazine and procainamide, the side effects due to sulphasalazine and the skin rash secondary to many sulphonamides.