Nat And Disease

The role of NATs in human disease has recently been extensively reviewed.[3] The following is a summation of findings to date. The association between acetylator status and the risk of various diseases has been extensively reported. Altered risk with either the slow or rapid phenotype has been observed for bladder, colon and breast cancer, systemic lupus erythematosis, diabetes, age-related cataracts, Gilbert's disease, Parkinson's disease, and Alzheimer's disease. These associations imply a role for environmental factors that are metabolized by the NATs, in particular NAT2, in each disorder. However, identifying those factors has remained elusive. Humans are exposed to many toxic NAT substrates including the food-derived heterocyclics present in the diet as well as arylamines such as 4-aminobiphenyl and p-naphthylamine present in tobacco smoke. Moreover, occupational exposure to arylamine carcinogens such as benzidine has also been reported.

Because of the role of acetylation in the metabolic activation and detoxification of arylamine and heterocy-clic carcinogens, acetylator status and cancer risk have been widely investigated. Unlike the relatively rare but highly penetrant genes involved in familial cancers, those genes responsible for metabolic polymorphisms have low penetrance and cause only a moderate increase in cancer risk. Nevertheless, their widespread occurrence in the general population suggests they are a significant contributor to individual risk. However, few diseases have consistently demonstrated a relationship between pheno-type and risk. For example, several studies have implicated the rapid phenotype as an increased risk factor for colon cancer,[15-17] whereas others have been unable to confirm this finding.[18-20] Geographical differences, ethnicity, lack of study power, dietary differences, and differences in other risk factors between study groups have been suggested as reasons for variable results from independent laboratories. Recent reports suggesting that NAT activity may be altered by environmental factors and substrate-dependent downregulation may also explain why inconsistent associations have been seen.

When acetylator phenotype has been linked to carcinogen exposure, more consistent results have been reported. For example, the rapid phenotype has emerged as a strong risk factor for colorectal cancer in those individuals who have a higher exposure to the food-derived heterocyclic amines. These observations provide strong circumstantial evidence that the heterocyclic amines have an important role in colorectal cancer, and extensive animal studies support this. They also illustrate the importance of establishing associations between genetic polymorphisms and disease risk. From such studies, it should be possible to pursue the causative agent(s) of the disease where no obvious candidate agent is evident.

Recently, the NAT2 acetylator phenotype has been linked to increased risk associated with neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. For late-onset Alzheimer's disease, an odds ratio of 3.0 (95% CI 1.3-7.3) has been reported for the rapid phenotype in non-apoE epsilon carriers.[21] By contrast, the slow phenotype appears to increase the risk of Parkinson's disease with an odds ratio of 3.58 (95% CI 1.96-6.56).[22] Although these results need to be confirmed with larger epidemiological studies, they point to environmental factors that are substrates for the NATs having a role in the onset of these diseases. Alternatively, the different alleles for NAT2 that produce the rapid or slow phenotype may cosegregate with unrelated genes that are the causative agent for the different neurodegen-erative diseases.

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