Chapter 43
Significance of Nitrosamines in Betel Quid Carcinogenesis
Downloaded via TUFTS UNIV on July 17, 2018 at 01:08:19 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
Bogdan Prokopczyk, Jacek Krzeminski, and Dietrich Hoffmann American Health Foundation, 1 Dana Road, Valhalla, NY 10595
Chewing betel quid has been estimated to be practiced by about 10% of the world's population (1). The high incidence of oral cancer in the Indian subcontinent has been causatively associated with this habit. The major carcinogens found in the saliva of betel quid chewers are three nitrosamines derived from Areca alkaloids (ADNA); 3(methylnitrosamino)propionitrile (MNPN) nitrosoguvacoline (NG), and nitrosoguvacine (NGC). Capillary GC-TEA analyses have indicated the for mation of additional nitrosamines in the saliva of betel quid chewers, namely, 3-(methylnitrosamino)propanal (MNPA), N-nitrosomethylethylamine, and 3(methylnitrosamino)propionicacid. The confirmation of the identity of these compounds by mass spectrometry is now in progress. MNPN is a strong carcinogen in F344 rats. Upon subcutaneous injec tion it elicits benign and malignant tumors of the esophagus, tongue, nasal cavity, and liver (2,3). MNPN was also tested for its tumor initiating activity on mouse skin and for its tumorigenic potential in the oral mucosa of rats (4). On mouse skin, MNPN showed only weak local tumor initiator activity. Twice daily swabbing of the oral cavity of rats with an aqueous solution of MNPN for up to 61 weeks led only to one oral tumor in 30 animals. Yet, regardless of the route of application, MNPN induced multiple distant tumors int he lungs, nasal cavity, liver and esophagus. MNPA is more cytotoxic to cultured human buccal epithelial cells than any other ADNA (5), and induces benign and malignant tumors in the lung of rats upon s.c. injection (6). Since MNPA-treated rats also developed tumors in the nasal cavity and in the liver, it appears that MNPA follows the pattern of other N-nitrosamines in terms of organ-specific carcinogenic activity. NG is weakly mutagenic to S.typhimurium TA1535 (7) and induces adenoma in the exocrine pancreas in rat (8). MNPN is the most powerful Areca-derived carcinogen found in the saliva of betel quid chewers at levels of 0.50-11.39 ng/mL. It is activated in vivo by α-hydroxylation thereby forming two electrophiles. Methyldiazohy droxide, which results from the methylene-carbon oxidation, can methylate nucleophilic centers in DNA. When α-hydroxylation occurs on the methyl group of MNPN 2-cyanoethyldiazohydroxide if formed. This unstable
0097-6156/94/0553-0365$08.00/0 © 1994 American Chemical Society
Loeppky and Michejda; Nitrosamines and Related N-Nitroso Compounds ACS Symposium Series; American Chemical Society: Washington, DC, 1994.
366
NITROSAMINES AND RELATED ΛΓ-NITROSO COMPOUNDS
metabolite also reacts with nucleophilic centers of D N A The formation of 7-methylguanine, 7-(2-cyanoethyl)guanine, Ο -methylguanine, and Ο -(2-cyanoethyl)guanine was detected in DNA of rats treated with MNPN (91 In rat liver DNA, the levels of 7-methylguanine were 3.3-7.5 times higher than ihose of 7-(2-cyanoethyl)guanine. In contrast, the extent of for mation of ) -(2-cyanoethyl)guanine was similar to that of Ο -methylguanine. However, this ratio does not directly reflect the rate of metabolism of MNPN to a methylating or cyanoethylating intermediate since both the extent of alkylation and the profile of alkylation products can differ considerably. In D N A isolated from the nasal mucosa, the ratios of 7-methylguanine:7-(2-cyanoethyl)guanine were considerably lower (1.5:2.2) and the extent of formation of cyanoethylated guanines was considerably higher, suggesting that in this organ MNPN is more extensively metabolized to the cyanoethylating inter mediate. Interestingly, the nasal mucosa was found to be a primary target tissue in the carcinogenicity assay. The involvement of pyanoethylated adducts in MNPN carcinogenicity requires further elucidation. ACKNOWLEDGEMENTS Supported by Grant CA-29580 from the National Cancer Institute. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9.
Fendell, L.D. and Smith, J.R. 1980, J. Oral Surg., 28: 455-456. Wenke, G., Rivenson, S., and Hoffmann, D. 1984, Carcinogenesis, 5: 1137-1140. Prokopczyk, B., Rivenson, A., Bertinato, P., Brunnemann, K.D., and Hoffmann, D. 1987, Cancer Res., 6: 467-471. Prokopczyk, B., Rivenson, A., and Hoffmann, D. 1991, Cancer Lett., 60: 153-157. Sudqvist, K., Liu, Y., Nair, J., Bartsch, H., Arvidson, K., and Grafstrom, R.C. 1989, Cancer Res., 49: 5294-5298. Nishikawa, A., Prokopczyk, B., Rivenson, A., Zang, E., and Hoffmann, D. 1992, Carcinogenesis, 13: 369-372. Rao, T.K., Hardigree, A.A., Young, J.A., Lijinsky, W., and Epler, J.L. 1977, Mutat. Res., 56: 131-145. Rivenson, A , Hoffmann, D., Prokopczyk, B., Amin, S., and Hecht, S.S. 1988, Cancer Res., 48: 6912-6917. Prokopczyk, B., Bertinato, P., and Hoffmann, D. 1988, Cancer Res., 48: 6780-6784.
RECEIVED January 31, 1994
Loeppky and Michejda; Nitrosamines and Related N-Nitroso Compounds ACS Symposium Series; American Chemical Society: Washington, DC, 1994.
