Prostate cancer (PC) is the second most frequently diagnosed cancer in men and the second leading cause of cancer deaths in men in the United States. Epidemiologic studies have linked frequent consumption of red meat with PC incidence; however, the mechanism(s) by which a meat diet leads to PC has not been established. Cooked meat containing carcinogenic heterocyclic aromatic amines (HAA) may contribute to PC risk. 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), an abundant HAA formed in cooked meat, is a rodent prostate carcinogen and classified as a possible human carcinogen (Group 2B) by IARC. Epidemiological studies have reported an association between frequent consumption of well-done cooked meats containing PhIP and PC risk. PhIP undergoes metabolic activation by cytochrome P450s, to form 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine (HONH-PhIP), which undergoes esterification by sulfotransferase (SULTs) or N-acetyltransferase (NATs) to form reactive intermediates that bind to DNA. Our research group recently identified DNA adducts of PhIP, but not adducts of other cooked meat HAA mutagens, including 2-amino-3,8-dimethylmidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-9H-pyrido[2,3-b]indole (AαC) in prostate biopsy samples of PC patients by liquid chromatography–mass spectrometry. We sought to understand why PhIP but not the other cooked meat mutagens induce DNA damage in human prostate. The cytotoxicity and DNA adducts of the genotoxic HONH-PhIP, HONH-MeIQx, HONH-IQ, and HONH-AaC metabolites were measured in the human prostate (LNCaP) cell line. HNOH-PhIP, but not other HONH-HAA, induced a concentration-dependent cytotoxicity in LNCaP cells. Moreover, PhIP DNA adduct formation was 20-fold greater than those adducts formed with other HONH-HAA. Chemical inhibitors showed that SULT1A1 accounted for about 40% of the PhIP-DNA binding, whereas NAT2 and NAT1 accounted for 40 and 20%, respectively. Our data provide support to the epidemiological observations implicating PhIP formed in well-done cooked meats as a DNA-damaging agent that may contribute to the etiology of prostate cancer

Mechanism of bioactivation of the cooked meat carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in human prostate

254th National Meeting (2017)

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