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

Human Tissue Studies Section, Laboratory of Experimental Pathology, Division of Cancer Cause and Prevention, National Cancer Institute, NIH, USPHS, Bethesda, Maryland 20205 [C. C. H., H. A., G. D. S.]; Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland 21201 [B. F. T., E. H.], Department of Surgery, Washington Veterans Administration Hospital, Washington, D. C. 20420 [P. W. S.], and Cancer Center/Institute of Cancer Research, Columbia University, New York, New York 10032 [A. M. J.]

The wide variation in the world-wide incidence of esophageal carcinoma suggests that environmental agents including chemicals 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 N-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 µM), [¹⁴C]DMN (100 µM), or [¹⁴C]N-nitrosopyrrolidine (100 µM) for 24 hr. Radioactivity was found bound to both mucosal protein (BP, DMN, and N-nitrosopyrrolidine) and DNA (BP and DMN). The major carcinogen-DNA adducts were: (a) with BP, N²-[10ß-(7ß,8,9-trihydroxy-7,8,9,10-tetrahydrobenzo(a)pyrenyl)]deoxyguanosine; and (b) with DMN, 7-methylguanine, and 0⁶-methylguanine (ratio of 0⁶-methylguanine 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 chromatographic patterns of water-soluble metabolites [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 metabolism and in carcinogen bound to esophageal DNA will play a role in human susceptibility to environmental chemical carcinogens is not as yet known.

¹ This work was supported in part by NIH Grants CA 21111 and CA 13696, NIH Contract N-01-CP 43237, and Interagency Agreement CP 60204.

² To whom requests for reprints should be addressed, at Laboratory of Experimental Pathology, Building 37, Room 3A07, National Cancer Institute, Bethesda, Md. 20205.

Received 4/25/79. Accepted 7/25/79.

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