DNA and protein adduct formation in the colon and blood of humans after exposure to a dietary-relevant dose of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine

Epidemiology studies have indicated that certain dietary components, includ ing well-cooked meat, are risk determinants for colon cancer. Cooked meat c an contain significant quantities of heterocyclic aromatic amines (HCAs), w hich have been established as carcinogens in laboratory animals, 2-Amino-1- methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is usually the most mass-abund ant HCA, with concentrations up to 480 ppb, We used accelerator mass spectr ometry to establish whether DNA and protein adducts can be detected in huma ns exposed to a quantity of PhIP comparable with levels of exposure that oc cur in the diet, Five human volunteers were administered a dietary-relevant dose of [C-14]PhIP (70-84 mu g) 48-72 h before surgery for removal of colo n tumors, Blood samples were collected at various time points, and albumin, hemoglobin, and WBC DNA were extracted for analysis by accelerator mass sp ectrometry, Tissue samples were collected during surgery and used to assess either tissue available doses of [C-14]PhIP or adduct levels, The results of this study show: (a) PhIP is activated to a form that will bind to album in, hemoglobin, and WBC DNA in peripheral blood, WBC DNA adducts were unsta ble and declined substantially over 24 h; (b) PhIP is bioavailable to the c olon, with levels in normal tissue in the range 42-122 pg PhIP/g tissue; an d (c) PhIP binds to both protein and DNA in the colon, DNA adduct levels in the normal tissue were 35-135 adducts/10(12) nucleotides, which was signif icantly lower than tumor tissue, The results of this study demonstrate that PhIP is bioavailable to the human colon following defined dietary-relevant doses and forms DNA and protein adducts.