Metabolism of Benzo(a)pyrene, JV-Nitrosodimethylamine, and A/-Nitrosopyrrolidine and Identification of the Major Carcinogen-DNA Adducts Formed in Cultured Human Esophagus1

The wide variation in the world-wide incidence of esophageal carcinoma suggests that environmental agents including chem icals cause this cancer. Since the interaction between chemical procarcinogens and human esophagus has not been studied previously, we examined the metabolic fate of benzo(a)pyrene (BP), N-nitrosodimethylamine (DMN), and A/-nitrosopyrrolidine in cultured nontumorous esophagus from two patients with and six patients without esophageal carcinoma. Esophageal explants were cultured in a chemically defined medium for 7 days prior to adding [3H]BP (1.5 JUM),[14C]DMN (100 /IM), or [14C]Nnitrosopyrrolidine (100 /¿M) for 24 hr. Radioactivity was found bound to both mucosal protein (BP, DMN, and A/-nitrosopyrrolidine) and DMA (BP and DMN). The major carcinogen-DNA adducts were: (a) with BP, N2-[10/?-(7/?,8a,9a-trihydroxy7,8,9,10-tetrahydrobenzo(a)pyrenyl)]deoxyguanosine; and (fa) with DMN, 7-methylguanine, and 06-methylguanine (ratio of O6methylguanine to 7-methylguanine was 0.3). The interindividual variations among people in binding levels to mucosal DNA were 99-fold for BP and 10-fold for DMN. In the two cases studied, the variation in binding levels among the three major anatomical segments (proximal, mid, and distal) was less than 2-fold. The metabolism of BP into water-soluble metabolites varied among the eight patients from 1 to 68% of the total metabolism. The qualitative Chromatographie patterns of water-soluble metabo lites [sulfate esters (range, 21 to 55%), glucuronide conjugates (7 to 37%), and glutathione conjugates (24 to 66%)] and of organic-extractable metabolites were similar in all patients. Whether or not quantitative differences in carcinogen metabo lism and in carcinogen bound to esophageal DNA will play a role in human susceptibility to environmental chemical carcin ogens is not as yet known.