Carcinogenic heterocyclic aromatic amines (HAA) are formed in cooked meats, poultry, and fish and arise in tobacco smoke. We measured the concentrations of four prevalent HAAs in spot urine samples collected at baseline from 170 participants of the Shanghai Cohort study, a population-based cohort study of adult men recruited during 1986 to 1989 in Shanghai, China. Sixteen (18.6%) of 86 nonsmokers were positive for urinary 2-amino-9H-pyrido[2,3-b]indole (AalphaC) versus 41 (48.8%) of 84 cigarette smokers; the difference was statistically significant (P < 0.001). The number of cigarettes smoked per day was positively and significantly related to urinary levels of AalphaC in study subjects (P < 0.001); the mean level among nonsmokers was 2.54 ng/g creatinine, whereas the means for light (1-19 cigarettes per day) and heavy (20+ cigarettes per day) smokers were 7.50 and 11.92 ng/g creatinine, respectively. 2-Amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline was undetected in the urine of the 170 subjects. Only 5 (2.9%) and 6 (3.5%) subjects, respectively, showed detectable levels of urinary 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, and smoking status was unrelated to levels of either HAA. Quantitative measurements of HAAs in commonly eaten pork and chicken dishes in Shanghai showed low concentrations of HAAs (<1 ng/g meat). Our data indicate that AalphaC represents a major HAA exposure in adult men of Shanghai, China, and that tobacco smoke is an important point source of their AalphaC exposure.
"Differences in meat cooking methods between Western and Asian populations may be another reason for the discrepancy. For example, in the US consuming grilled meat is a major source of exposure to the colorectal mutagens, heterocyclic amines (Bogen and Keating, 2001), whereas these are at non-detectable levels among Chinese populations, where stir frying is the preferred meat cooking method (Turesky et al, 2007). "
[Show abstract][Hide abstract] ABSTRACT: An influence of Western diet and lifestyle factors observed among Singapore Chinese may contribute to the population's marked rise in colorectal cancer incidence over the past two decades. Thus far, however, there is little evidence for individual nutrients and foods as major contributing factors in this population. We evaluated whether patterns of food intake were associated with colorectal cancer in a population-based cohort of 61,321 Singapore Chinese that was established in 1993-98. Two dietary patterns, meat-dim sum and vegetable-fruit-soy, were previously identified by principal components analysis using baseline dietary data from a validated 165-item food frequency questionnaire. As of 31 December 2005, 961 incident colorectal cancer cases were diagnosed. Proportional hazards regression was used to calculate adjusted hazard ratios. Using nearly 10 years of follow-up data, we observed no association with either the meat-dim sum or vegetable-fruit-soy pattern for colorectal cancer. In conclusion, neither individual nutrients or foods nor dietary patterns appear to explain the rise in colorectal cancer among Singapore Chinese population.
British Journal of Cancer 10/2008; 99(9):1511-6. DOI:10.1038/sj.bjc.6604678 · 4.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 2-amino-9H-pyrido[2,3-b]indole (AalphaC) is a carcinogenic heterocyclic aromatic amine (HAA) that is produced in high quantities in tobacco smoke and that also forms in charred meats. The bioactivation of AalphaC occurs by cytochrome P450-mediated (P450 1A2) N-oxidation of the exocyclic amine group, to form 2-hydroxyamino-9H-pyrido[2,3-b]indole (HONH-AalphaC). The HONH-AalphaC metabolite can then undergo further activation by phase II enzymes to form the penultimate ester species, which bind to DNA. Some epidemiological studies suggest a role for NAT2 genetic polymorphisms in human susceptibilities to various cancers from tobacco smoke and from consumption of well-done meats, where the exposures to AalphaC can be substantial. In this investigation, we have measured the genotoxicity of AalphaC in nucleotide excision repair-deficient Chinese hamster ovary (CHO) cells stably transfected with human P450 1A2 and either the NAT2*4 (rapid, wild-type acetylator) or the NAT2*5B (the most common slow acetylator) allele, to determine the role of NAT2 phenotype in the biological effects of AalphaC. Mutations at the hypoxanthine phosphoribosyl transferase (hprt) locus were induced in a dose-dependent manner by AalphaC and were found to be highest in cells transfected with P450 1A2 and NAT2*4, followed by cells transfected with P450 1A2 and NAT2*5B. The level of formation of the deoxyguanosine (dG) adduct N-(deoxyguanosin-8-yl)-2-amino-9H-pyrido[2,3-b]indole (dG-C8-AalphaC) paralleled the mutagenic potency in these cell lines. However, AalphaC did not form DNA adducts or induce mutations in untransfected CHO cells or in cells only expressing P450 1A2. These findings clearly demonstrate that NAT2 genetic polymorphism plays a major role in the genotoxic potency of AalphaC.
Chemical Research in Toxicology 03/2009; 22(4):726-33. DOI:10.1021/tx800473w · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: N-acetyltransferases (NAT) 1 and 2 are polymorphic enzymes catalyzing the metabolic activation of heterocyclic amines. We investigated the modifying effects of NAT1 and NAT2 polymorphisms on the association of meat consumption, heterocyclic amine intake, and smoking with colorectal cancer risk.
In the Multiethnic Cohort study, participants completed a smoking history and a food-frequency questionnaire at recruitment and a cooked meat module 5 years later to estimate heterocyclic amine intake (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline). Blood samples were collected from incident cases and age-, sex-, ethnicity-, frequency-matched controls to determine genotypes. For analysis of meat intake and smoking, data were available for 1,009 cases and 1,522 controls; for heterocyclic amine intake analyses, 398 cases and 1,444 controls were available. Multivariate logistic regression models were used to estimate odds ratios.
Smoking was associated with an increased colorectal cancer risk (odds ratio, 1.51; 95% confidence interval, 1.17-1.95) for > or =30 pack-years compared with never smokers (P trend = 0.0004). The association was stronger with presence of the "rapid" compared with the "slow/intermediate" NAT2 genotype (P interaction = 0.003). No significant associations were observed for intakes of red meat, processed meat, and heterocyclic amine, or meat doneness preference, but a dietary pattern high in meat showed a weak positive interaction with the NAT2 genotype (P interaction = 0.05).
The enhanced association between smoking and colorectal cancer risk in subjects with the NAT2 rapid genotype supports a role for NAT2 and tobacco smoke heterocyclic amines in the etiology of colorectal cancer. This study only provides weak support for a similar association with meat heterocyclic amines.
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