Red wine consumption is inversely associated with 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine-DNA adduct levels in prostate

Abstract

In humans, genetic variation and dietary factors may alter the biological effects of exposure to 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), one of the major heterocyclic amines generated from cooking meats at high temperatures that has carcinogenic potential through the formation of DNA adducts. Previously, we reported grilled red meat consumption associated with PhIP-DNA adduct levels in human prostate. In this study, we expanded our investigation to estimate the associations between beverage consumption and PhIP-DNA adduct levels in prostate for 391 prostate cancer cases. Of the 15 beverages analyzed, red wine consumption had the strongest association with PhIP-DNA adduct levels showing an inverse correlation in both tumor (P = 0.006) and nontumor (P = 0.002) prostate cells. Red wine consumption was significantly lower in African American compared with white cases, but PhIP-DNA adduct levels in prostate did not vary by race. In African Americans compared with whites, however, associations between red wine consumption and PhIP-DNA adduct levels were not as strong as associations with specific (e.g., SULT1A1 and UGT1A10 genotypes) and nonspecific (e.g., African ancestry) genetic variation. In a multivariable model, the covariate for red wine consumption explained a comparable percentage (13%-16%) of the variation in PhIP-DNA adduct levels in prostate across the two racial groups, but the aforementioned genetic factors explained 33% of the PhIP-DNA adduct variation in African American cases, whereas only 19% of the PhIP-DNA adduct variation in whites. We conclude that red wine consumption may counteract biological effects of PhIP exposure in human prostate, but genetic factors may play an even larger role, particularly in African Americans.

Figure 1

Mixed model estimated PhIP-DNA adduct level means and standard errors stratified by cell type (non-tumor/tumor), race (white/black), grilled meat intake (high/low) and red wine consumption (yes/no). Model adjusted for tumor grade, tumor volume and batch effects. Listed p values (* p<0.05; ** p<0.01) are for comparisons of each meat/red wine consuption group with the high grilled meat intake/no red wine consumption group within each cell type/race stratum.

Figure 2

2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), is the major genotoxic heterocyclic amine generated from cooking meats at high temperatures. PhIP is metabolized by CYP forms to its active intermediate, N-Hydroxy-PhIP, which can then be detoxified through conjugation by various UDP-glucuronosyltransferase (UGT) forms to PhIP-N2-glucuronide and PhIP-N3-glucuronide. Alternatively, N-Hydroxy-PhIP can undergo sulfation to form N²-Sulfonyloxy-PhIP, which can bind DNA to form carcinogen adducts. Reseveratrol is also a substrate for sulfotransferases, and can competitively inhibit the activation of PhIP via this pathway. We also hypothesize that other genetic factors related to African ancestry interact with the glucuronidation and sulfation pathways of N-Hydroxy-PhIP metabolism. Note that we depict only one branch of the PhIP metabolic pathway in this figure and further note that SULT1A1 can also react with N-hydroxy-PhIP to form 4'-SO₄-PhIP that is excreted in urine.