Meat mutagens and risk of distal colon adenoma in a cohort of US men

Department of Nutrition, Harvard School of Public Health, Building 2, 665 Huntington Avenue, Boston, MA 02115, USA.
Cancer Epidemiology Biomarkers & Prevention (Impact Factor: 4.13). 07/2006; 15(6):1120-5. DOI: 10.1158/1055-9965.EPI-05-0782
Source: PubMed


Cooking meats at high temperatures and for long duration produces heterocyclic amines and other mutagens. These meat-derived mutagenic compounds have been hypothesized to increase risk of colorectal neoplasia, but prospective data are unavailable. We examined the association between intakes of the heterocyclic amines 2-amino-3,8-dimethylimidazo[4,5,-f]quinoxaline (MeIQx), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-3,4,8-trimethylimidazo[4,5,-f]quinoxaline (DiMeIQx), and meat-derived mutagenicity (MDM) and risk of distal colon adenoma using a cooking method questionnaire administered in 1996 in the Health Professionals Follow-up Study cohort. Between 1996 and 2002, 581 distal colon adenoma cases were identified. Higher intake of MDM was marginally associated with increased risk of distal adenoma [fourth versus lowest quintile: odds ratio (OR), 1.39; 95% confidence interval (95% CI), 1.05-1.84; highest versus lowest quintile: OR, 1.29; 95% CI, 0.97-1.72; P(trend) = 0.08]. Adjusting for total red meat or processed meat intake did not explain those associations. Our data also suggested a positive association between higher MeIQx (highest versus lowest quintile: OR, 1.28; 95% CI, 0.95-1.71; P(trend) = 0.22) and risk of adenoma, but this association was attenuated after adjusting for processed meat intake. DiMeIQx and PhIP did not seem to be associated with risk of adenoma. In conclusion, higher consumption of mutagens from meats cooked at higher temperature and longer duration may be associated with higher risk of distal colon adenoma independent of overall meat intake. Because mutagens other than heterocyclic amines also contribute to MDM, our results suggest that mutagens other than heterocyclic amines in cooked meats may also play a role in increasing the risk of distal adenoma.

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    • "Epidemiological studies in the past indicate that a correlation between the consumption of high amounts of strongly heated red meat and the development of colorectal cancer may in fact exist (Scheppach et al., 1999; Chao et al., 2005; Norat et al., 2005; Sinha et al., 2005; Wu et al., 2006; Rohrmann et al., 2007). As to the compounds possibly being involved in the malignant transformation of epithelial cells in the colon and rectum, a number of toxic substances, including the heterocyclic aromatic amines (HCAs), have been identified in heated red meat. "
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    ABSTRACT: Previous studies have shown that in the rat, the colon carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is only absorbed to a limited extent in the small intestines and that a major fraction of unmetabolised PhIP reaches the colon. Moreover, PhIP is extensively metabolised when incubated with human stool samples to a major derivative, 7-hydroxy-5-methyl-3-phenyl-6,7,8,9-tetrahydropyrido [3',2':4,5]imidazo[1,2-a]pyrimidin-5-ium chloride (PhIP-M1). In the present study, the uptake and transport of PhIP-M1 in Ussing chamber experiments, its cytotoxicity in the different segments of the Fischer 344 rat gut and its transforming potential in the BALB/c 3T3 cell transformation assay were analysed. At the most, 10-20% of the PhIP-M1 amount added to the mucosal compartment of the Ussing chambers per segment were absorbed within 90min. Therefore, the amount of PhIP-M1 detected in the tissues as well as in the serosal compartment of the Ussing chambers was extremely low. Moreover, human-relevant concentrations of PhIP-M1 were not cytotoxic and did not induce the malignant transformation of BALB/c 3T3 cells. In conclusion, even if one would assume that 100% of the daily amount of PhIP ingested by a human being is converted into PhIP-M1 in the colon, this concentration most probably would not lead to cytotoxicity and/or carcinogenicity in the colorectal mucosa. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Toxicology Letters 02/2015; 234(2):92-98. DOI:10.1016/j.toxlet.2015.02.015 · 3.26 Impact Factor
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    • "Since humans take up less than 1 lg HCAs per day (SKLM 1998), even if one supposed that 100 % of the daily amount of PhIP ingested by a human being is converted into PhIP-M1 in the colon, the concentration needed to induce DNA damage in the epithelial cells of the colonic mucosa is definitely not reached. A number of epidemiological studies have pointed out that a positive association between the consumption of red and processed meat and colorectal cancer risk exists (Scheppach et al. 1999; Chao et al. 2005; Norat et al. 2005; Sinha et al. 2005; Wu et al. 2006; Rohrmann et al. 2007). Furthermore, it has been postulated that haem iron, nitrate/ nitrite as well as HCAs present in red and processed meat might explain the above-mentioned association (Cross et al. 2010). "
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    ABSTRACT: Epidemiological studies show that a positive correlation exists between the consumption of strongly heated meat and fish and the development of colorectal tumours. In this context, it has been postulated that the uptake of toxic substances formed during meat and fish processing such as heterocyclic aromatic amines (HCAs) may be causally related to colon carcinogenesis. In a previous study, we have shown that 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), the most abundantly formed HCA in the above-mentioned food items, is mainly absorbed in the small intestine (i.e. proximal jejunum) of the rat. In the present study, we analysed whether PhIP can actively be secreted by enterocytes in the rat proximal jejunum and distal colon. Unidirectional PhIP flux rates from the mucosal-to-the serosal compartment (J ( ms )) and in the opposite direction (J ( sm )) were examined in Ussing chambers with (14)C-PhIP as radiotracer and in the absence of electrochemical gradients. Under these experimental conditions, significant negative net flux rates (J ( net ) = J ( ms ) - J ( sm )) can only be explained by an active secretion of PhIP into the luminal compartment, and such an effect was observed in the rat distal colon, but not in the proximal jejunum. Moreover, the data obtained suggest that the breast cancer resistance protein, the multidrug resistance protein 4 and P-glycoprotein are not involved in the active secretion of PhIP in the rat distal colon. The potential role of PhIP transport in colon carcinogenesis is discussed.
    Archives of Toxicology 01/2013; 87(5). DOI:10.1007/s00204-012-1006-0 · 5.98 Impact Factor
    • "Several epidemiological studies in different countries have shown that a correlation between the consumption of processed (i.e. strongly heated) meat and the induction of certain cancer types in humans does in fact exist (Chao et al., 2005; Norat et al., 2005; Sinha et al., 2005; Wu et al., 2006). By cooking meat at high temperatures for a long time or over an open fire heterocyclic aromatic amines (HCAs) are formed. "
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    ABSTRACT: 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a colon carcinogen in rats. In the present study the absorption of PhIP in the small and large intestine of Fischer 344 rats was determined, and the relevance of the differences in the degree of absorption of PhIP along the gastrointestinal axis for the PhIP-mediated colon carcinogenesis process is discussed. PhIP uptake was low in the different gut sections of Fischer 344 rats, the PhIP tissue levels varying in the following order: proximal jejunum>distal jejunum>proximal colon>distal colon=rectum. Furthermore, abcc2 was mainly expressed in the proximal parts of the small intestine, in particular in the proximal jejunum. Extremely low expression levels were observed in distal jejunum, ileum, caecum and proximal colon, whereas abcc2 was almost not detected in distal colon and rectum. These data, together with previously published results, lend support to the hypothesis that PhIP is taken up in the proximal segments of the small intestine and after being metabolically activated in the liver reaches the stem cell compartment of the colonic crypts via the blood circulation, the crypt cells in the distal colon and rectum being particularly at risk, since these almost do not express abcc2.
    Toxicology Letters 04/2010; 196(1):60-6. DOI:10.1016/j.toxlet.2010.04.002 · 3.26 Impact Factor
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