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Cytotoxic and Genotoxic Effects of Areca Nut-related Compounds in Cultured Human Buccal Epithelial Cells¹

Department of Toxicology, Karolinska Institutet, Box 60400, S-104 01 Stockholm, Sweden [K. S., Y. L., R. C. G.]; Unit of Environmental Carcinogens and Host Factors, International Agency for Research on Cancer, 150 Cours Albert-Thomas, 69372 Lyon Cedex 08, France [J. N., H. B.]; and Department of Prosthetic Dentistry, Karolinska Institutet, S-141 04 Huddinge, Sweden [K. A.]

Because betel quid chewing has been linked to the development of oral cancer, pathobiological effects of an aqueous areca nut extract, four areca nut alkaloids (arecoline, guvacoline, guvacine, and arecaidine), and four nitrosated derivatives [N-nitrosoguvacoline, N-nitrosoguvacine, 3-(N-nitrosomethylamino)propionaldehyde and 3-(N-nitrosomethylamino)propionitrile] have been investigated using cultured human buccal epithelial cells. Areca nut extract in a dose-dependent manner decreases cell survival, vital dye accumulation, and membrane integrity, and it causes formation of both DNA single strand breaks and DNA protein cross-links. Depletion of cellular free low-molecular-weight thiols also occurs, albeit at quite toxic concentrations. Comparisons of the areca nut-related N-nitroso compounds and their precursor alkaloids, at concentrations up to 5 mM, indicate that 3-(N-nitrosomethylamino)propionaldehyde is the most potent on a molar basis to decrease both survival and thiol content and to cause significant formation of DNA single strand breaks. Arecoline, guvacoline, or N-nitrosoguvacoline decreases survival and cellular thiols, whereas arecaidine, guvacine, N-nitrosoguvacine, and 3-(N-nitrosomethylamino)propionitrile have only minor effects on these variables. Taken together, the present studies indicate that aqueous extract and, in particular, one N-nitroso compound related to areca nut, i.e., 3-(N-nitrosomethylamino)propionaldehyde, are highly cytotoxic and genotoxic to cultured human buccal epithelial cells, of potential importance in the induction of tumors in betel quid chewers.

¹ Supported in part by grants from the Swedish National Board of Laboratory Animals, the Swedish Tobacco Company, the Swedish Cancer Society, the Swedish Natural Science Research Council, the Swedish Medical Research Council, and the Swedish Fund for Scientific Research Without Animal Experiments, by funds from the Karolinska Institute, and by NIH Grant 1001 CA 43176-01 from the USPHS.

² To whom correspondence should be addressed, at Department of Toxicology, Karolinska Institutet, Box 60400, S-104 01 Stockholm, Sweden.

Received 2/ 3/89. Revised 6/26/89. Accepted 7/ 5/89.

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