Red meat intake, NAT2, and risk of colorectal cancer: a pooled analysis of 11 studies.

BACKGROUND: Red meat intake has been associated with risk of colorectal cancer, potentially mediated through heterocyclic amines. The metabolic efficiency of N-acetyltransferase 2 (NAT2) required for the metabolic activation of such amines is influenced by genetic variation. The interaction between red meat intake, NAT2 genotype, and colorectal cancer has been inconsistently reported. METHODS: We used pooled individual-level data from the Colon Cancer Family Registry and the Genetics and Epidemiology of Colorectal Cancer Consortium. Red meat intake was collected by each study. We inferred NAT2 phenotype based on polymorphism at rs1495741, highly predictive of enzyme activity. Interaction was assessed using multiplicative interaction terms in multivariate-adjusted models. RESULTS: From 11 studies, 8,290 colorectal cancer cases and 9,115 controls were included. The highest quartile of red meat intake was associated with increased risk of colorectal cancer compared with the lowest quartile [OR, 1.41; 95% confidence interval (CI), 1.29-1.55]. However, a significant association was observed only for studies with retrospective diet data, not for studies with diet prospectively assessed before cancer diagnosis. Combining all studies, high red meat intake was similarly associated with colorectal cancer in those with a rapid/intermediate NAT2 genotype (OR, 1.38; 95% CI, 1.20-1.59) as with a slow genotype (OR, 1.43; 95% CI, 1.28-1.61; P interaction = 0.9). CONCLUSION: We found that high red meat intake was associated with increased risk of colorectal cancer only from retrospective case-control studies and not modified by NAT2 enzyme activity. IMPACT: Our results suggest no interaction between NAT2 genotype and red meat intake in mediating risk of colorectal cancer.

Crystal structure of arylamine N-acetyltransferases: insights into the mechanisms of action and substrate selectivity.

INTRODUCTION: Arylamine N-acetyltransferases (NATs) are polymorphic xenobiotic metabolizing enzymes catalyzing the acetylation of aromatic amine chemicals of pharmacological/toxicological relevance (drugs, carcinogens). NATs are primordial determinants of the detoxification and/or bioactivation of these compounds. These enzymes are found in prokaryotes and eukaryotes. Several NAT isoenzymes may be present in one organism, and their substrate specificity profile and pattern of tissue expression suggest distinct functional roles. AREAS COVERED: Many advances in NAT mechanism, substrate specificity, and functional impact of polymorphism have come from crystallographic and NMR studies. To date, the crystal structures of 10 different NAT homologues have been solved, including two human isoforms and several bacterial NATs. The authors present the most recent snapshot in NAT structure differences and similarities. The authors also depict the structural bases of substrate/inhibitor recognition and specificity, cofactor binding, catalytic mechanism, genetic regulation (polymorphism), and enzyme inhibition. EXPERT OPINION: The determination of other NATs structures will help to develop specific inhibitors of NAT enzymes with potential clinical relevance. In addition, it will contribute to the identification of endogenous substrates and novel functions associated to this family of enzymes.

Association of NAT2 and smoking in relation to breast cancer incidence in a population-based case-control study (United States).

OBJECTIVE: To evaluate the potential interaction between N-acetyltransferase 2 (NAT2) and smoking in breast cancer incidence. METHODS: The data are derived from a population-based case-control study of women aged 20-69 years who were residents of Massachusetts or Wisconsin during 1997-1998. Incident cases of invasive breast cancer were identified through state tumor registries and age-similar controls were selected at random from population lists. Telephone interviews were conducted to obtain information on known and suspected risk factors including smoking history. Women provided oral mucosal DNA through the mail for genetic studies. RESULTS: A total of 791 cases and 797 controls were included in the analysis. Overall, smoking was modestly associated with breast cancer risk (multivariate odds ratio (OR) for ever smoking: 1.37; 95% confidence interval (CI): 1.12-1.69), and there was a trend in risk for greater pack-years of smoking among postmenopausal women (p for trend = 0.02). Overall, NAT2 was not related to invasive breast cancer (multivariate OR: 1.1 1; 95% CI: 0.90-1.36). Associations of smoking with breast cancer tended to be somewhat stronger among the women with the slow acetylator genotype for NAT2: when compared to those who never smoked and were rapid acetylators, the OR for ever smoking was 1.50 (95% CI: 1.11-2.02) in slow acetylators, and OR: 1.24 (95% CI: 0.91-1.70) in rapid acetylators. However, tests for multiplicative interaction were not significant in case-control comparisons, or in case-only analyses. CONCLUSION: Results of the study are compatible with the majority of previous studies that indicate little or no association of NAT2, smoking, or their interaction with the occurrence of breast cancer.

Role of N-acetyltransferase phenotypes in bladder carcinogenesis: a pharmacogenetic epidemiological approach to bladder cancer.

A large excess of patients with bladder cancer who have previously been exposed to N-substituted aryl compounds as a result of the production of dyestuff intermediates have the slow phenotype of the enzyme N-acetyltransferase. Among bladder-cancer patients in general, those presenting with T3 or T4 disease or carcinoma-in-situ also show an excess of the slower subtypes. Either N-substituted aryl compounds more frequently produce tumours with this invasive potential if linked with slow acetylation or slow acetylators are more susceptible to tumour production when exposed to some N-substituted aryl compounds. It is suggested that acetylator status could be used to identify susceptible individuals in potentially hazardous occupations.