Well-done red meat, metabolic phenotypes and colorectal cancer in Hawaii

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Abstract

Heterocyclic amines (HAAs) and polycyclic hydrocarbons are suspected colorectal cancer (CRC) carcinogens that are found in well-done meat. They require metabolic activation by phase I enzymes, such as the smoking-inducible CYP1A isoenzymes. N-acetyltransferase 2 (NAT2) also play a role in the further activation of HAAs. We conducted a population-based case-control study in Hawaii to test the associations of preference for well-done red meat and HAA intake with colon and rectal cancers, as well as the modifying effects of NAT2 and CYP1A2. We interviewed 727 Japanese, Caucasian or Native Hawaiian cases and 727 controls matched on sex, age, and ethnicity. HAA intake was estimated based on consumption of meat and fish for each of several cooking methods and doneness levels. A subgroup of 349 cases and 467 controls was phenotyped for CYP1A2 by a caffeine test. We found that preference for well-done red meat was associated with a 8.8-fold increased risk of CRC (95% CI: 1.7–44.9) among ever-smokers with the NAT2 and CYP1A2 rapid phenotypes, compared to ever-smokers with low NAT2 and CYP1A2 activities and who preferred their red meat rare or medium. A dose-dependent association was also found between the HAA intake estimates and male rectal cancer, with a two- to three-fold increase in risk from the low (T1) to high (T3) tertile of intake for each HAA. This association was strongest for MeIQx. HAA intake was not associated with male colon cancer or colon or rectal cancer in women. These data provide support to the hypothesis that exposure to pyrolysis products through consumption of well-done meat increases the risk of CRC, particularly in individuals who smoke and are genetically susceptible (as determined by a rapid phenotype for both NAT2 and CYP1A2). An attempt to examine the risk associated with specific HAAs suggested that the main HAAs increase risk of rectal cancer in men and that they do not appreciably affect risk of rectal cancer in women or of colon cancer in either sex.

Introduction

Recent evaluations of the epidemiologic literature on meat and colorectal cancer (CRC) have concluded that high red meat diets probably increase the risk of this disease [1], [2], [3]. These foods, especially when cooked well-done, may be a source of exposure to chemical carcinogens, such as heterocyclic aromatic amines (HAAs), polycyclic aromatic hydrocarbons (PAHs) and other pyrolysis products [4]. A number of HAAs have been identified in cooked meat and fish at levels that vary according to cooking methods, temperature and duration, and type of meat [5], [6]. 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (Di-MeIQx) are the most significant HAAs in terms of human exposure and carcinogenic potency [6].

Before they can bind to DNA, HAAs require metabolic activation through N-oxidation by cytochrome P450 enzymes of the 1A family (CYP1A2 in particular), followed by O-esterification by N-acetyltransferase-2 (NAT2) [7]. A number of single nucleotide polymorphisms (SNPs) have been identified in the NAT2 gene which result in alleles coding for decreased enzyme activity, five of which (5A, 5B, 5C, 6A, 7B) occur with significant frequency (> 1%) [8]. These polymorphisms explain most of the inter-individual variation in NAT2 activity. The CYP1A2 gene is also thought to be polymorphic; however, none of the genetic variants described to date has been clearly demonstrated to explain the inter-individual variation in CYP1A2 activity [9], [10]. Thus, pharmacologic probes (e.g. caffeine) have been used to characterize individuals for CYP1A2 phenotype [11]. CYP1A2 is also known to be inducible by a number of environmental exposures including smoking [11]. It has been hypothesized that the rapid NAT2 phenotype confers an increased CRC risk, especially when combined with the rapid CYP1A2 phenotype and consumption of well-done meat [11]. Recent studies, which examined the association of NAT2 alone or in combination with some measure of meat or well-done meat intake, have only been weakly supportive of the hypothesis [12]. More striking were the results of Lang et al. [11] who assess both NAT2 and CYP1A2 activities and found a 6.45-fold increased CRC risk in subjects with both the rapid NAT2 and rapid CYP1A2 phenotypes and preference for well-done meat. We recently replicated these findings in a large population-based case-control study in Hawaii [13]. Here, we further report on this study, presenting data separately for colon and rectal cancers, two cancer sites which do not have identical risk factors, and comparing the findings obtained for well-done meat and HAAs.

Section snippets

Methods

Methods for this study were described in detail elsewhere [13]. Cases were identified through the rapid reporting system of the Hawaii SEER Registry and consisted of Caucasian, Japanese or Native Hawaiian residents of the Island of Oahu diagnosed with a primary CRC between January 1994 and August 1998. Controls were selected from participants in an on-going population-based health survey conducted by the Hawaii State Department of Health, or from Health Care Financing Administration

Results

The characteristics of cases and controls were published previously [13]. Sixty percent of the subjects were Japanese, 26% Caucasian and 14% Hawaiian. Japanese were found to be more likely to prefer their red meat well-done or very well-done in the present study (27.5% versus 17.1% for Caucasians and 23.4% for Hawaiians). Table 1 shows odds ratios for increasing tertile of (total) red meat intake and for red meat preference by subsite of the large bowel. Red meat intake was unrelated to colon

Discussion

Hawaii’s population appears to be particularly suitable for studying the HAA–CRC association since Hawaii Japanese are a large group and have a very high risk for CRC and a high prevalence for the rapid NAT2 phenotype [20]. They also consume high amounts of red meat [20]. Other studies in Hawaii have also suggested that beef intake, either as main effect or combined with a family history of CRC, is a particularly strong risk factor for CRC in this population [21], [22].

The present study was

Acknowledgements

Supported in part by grant R01-CA60987 and contract N01-CN55424 from the National Cancer Institute, US Department of Health and Human Services. The authors thank the Hawaii Tumor Registry, Castle Medical Center, Kaiser-Permanente Medical Center, Kuakini Medical Center, Queen’s Medical Center, Straub Clinic and Hospital, St. Francis Medical Center, and Wahiawa General Hospital for their collaboration. The content of this paper is solely the responsibility of the authors and does not necessarily

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