Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
Modification by N-acetyltransferase 1 genotype on the association between dietary heterocyclic amines and colon cancer in a multiethnic study
Introduction
Colorectal cancer incidence rates have been declining in the U.S., with the steepest decline since 1990, especially among non-Hispanic whites [1]. Incidence rates (100,000/year) between 2000 and 2004 were higher among African-American males (72.6) and females (55.0), compared to whites males (60.4) and females (44.0) [2]. Contributing factors to the higher rates of colorectal cancer among African Americans may include dietary intake [3] and/or eating behavior [4], genetic variation at metabolic loci [5] and/or joint effects of both dietary factors and genetic susceptibility [6].
Heterocyclic amines (HCAs) are mutagens and animal carcinogens that are formed when meat is cooked at high temperatures by methods such as pan frying until it is well-done or has a charred appearance [7]. Consumption of pan-fried, well-done meat is a surrogate for HCA and PAH exposure [8], and may be positively associated with colon cancer [9]. Differences in meat intake patterns by doneness and cooking method have been observed among a population-based control sample of African Americans and whites in North Carolina, U.S. For example, among African-American controls, greater intake was observed for pan-fried red meat, well/very well-done red meat, white meat and pan-fried chicken intake, and the HCAs, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), and 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx), compared to white controls. In contrast, greater grilled/barbecued red meat intake was observed among white controls, compared to African-American controls [10].
HCAs require activation in order to exhibit carcinogenic potential [11]. The initial N-hydroxylation step occurs in the liver, and is catalyzed by cytochrome p4501A2 (CYP1A2) [12]. The resulting N-hydroxy HCA derivatives are thought to be stable enough to circulate to the colon [13], [14] where they are activated by N-acetyltransferase 1 (NAT1) and 2 (NAT2) through O-acetylation leading to the formation of highly reactive N-acetoxy esters [15]. These compounds undergo spontaneous hydrolysis to form arylnitrenium ions; which have the potential to covalently bond with DNA to form adducts and thereby increase risk of mutagenesis and possibly colon cancer [16], [17]. NAT1 and NAT2 expression in hepatic, as well as extrahepatic human tissues has been well documented, with recent mRNA localization to the surface epithelial cells of the colon and of the crypts of Lieberkuhn [18].
Interindividual differences in the acetylation or metabolic activation of HCAs have been reported [19]. In addition, NAT1 and NAT2 genotype frequencies vary by race [19], [20], suggesting that racial differences in genetic susceptibility to HCAs may contribute to differences in colorectal cancer risk. Although several epidemiologic studies have evaluated whether genetic susceptibility at the NAT loci modify the association between surrogates of HCA exposure (e.g. meat doneness or cooking method) on risk of colon cancer [21], [22], [23], [24], few data are available that measure individual HCA compounds in a multiethnic population-based sample. We investigated whether our previously reported findings [10] were modified by NAT1 or NAT2 genotype, and whether there were differences by race.
Section snippets
Study population
Cases and controls of the North Carolina Colon Cancer Study were selected from 33 counties in North Carolina, U.S., and frequency matched to cases by race (African American, white), age (<65, ≥65 years), and sex [25]. Details of the study design have been previously described [10]. In brief, cases were selected through a rapid ascertainment system [26] established in conjunction with the North Carolina Central Cancer Registry. Cases were eligible if they were between 40 and 84 years of age at
Results
NAT1 and NAT2 allele and genotype frequencies are presented in Table 1. Genotype frequencies among controls were in HWE for NAT1 (P = 0.98 among African Americans, P = 0.65 among whites, with d.f. = 3), and for NAT2 (P = 0.55 among African Americans, P = 0.80 among whites, with d.f. = 4). Among controls, we observed higher frequencies of the NAT1*10, NAT2-rapid, and NAT2-intermediate genotypes among African Americans, than among whites. There was no association with colon cancer for NAT1*10 versus
Discussion
Racial disparities for colon cancer cannot be explained solely by socioeconomic, behavior, environmental, lifestyle factors, or genetic factors, rather explanations for these disparities may include interactions between all of these factors [41]. Using data from a population-based case-control study, we observed statistically significant interaction between meat-derived HCA intake and NAT1 genotype, regardless of race. In addition, our data suggest that NAT1 acetylation of HCAs differs by race,
Acknowledgements
This research was supported, in part, by grants from the National Institutes of Health T32 DK07634, R01 CA66635, P30-DK34987, NIEHS P30-ES10126, and P30-CA16086.
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