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© 1989 Oxford University Press

research-article

Inhibition by lipoxygenase inhibitors of 7-bromomethylbenz[a]anthracene-caused epidermal ornithine decarboxylase induction and skin tumor promotion in mice

Teruo Nakadate 1, Satoshi Yamamoto 2, Eriko Aizo and Ryuichi Kato

Department of Pharmacology, School of Medicine, Keio University 35 Shinanomachi, Shinjuku-tu, Tokyo 160, Japan
1Present address: Laboratory of Pharmacology, Basic Research Laboratories, Toray Industries, Inc. 1111 Tebiro, Kamakura, Kanagawa 248, Japan

2To whom correspondence should be addressed

7-Bromomethylbenz[a]anthracene (BrMBA) has been shown to have a tumor-promoting action in mouse skin without an initial direct interaction with protein kinase C, which is believed to be a receptor for phorbol ester tumor promoters such as 12-0-tetradecanoylphorbol-13-acetate (TPA). An application of BrMBA to mouse dorsal skin caused epidermal ornithine decarboxylase (ODC) induction in a dose-dependent manner with a peak of activity at 12 h after the application. A single topical application of BrMBA failed to induce mouse ear edema formation, i.e. inflammation. However, repeated applications of BrMBA, i.e. twice a week for 3–4 times, caused a significant edema. Unlike TPA, BrMBA failed to stimulate the superoxide anion generation of rabbit peritoneal polymorphonuclear leukocytes. Lipoxygenase inhibitors such as 3,4,2',4'-tetrahydroxychalcone, nordihydroguaiaretic add, quercetin and 2,3,5-trimethyl-6-(12-hydroxy-5,10-dode-cadiynyl)-1,4-benzoquinone (AA861) effectively inhibited BrMBA-caused epidermal ODC induction and ear edema formation. In addition, BrMBA-caused skin tumor promotion was also potently inhibited by 3,4,2',4'-tetrahydroxy-chalcone and quercetin. These results indicate that a mechanism susceptible to lipoxygenase inhibitors plays a role not only in the TPA-caused but also in the BrMBA-caused epidermal ODC induction, skin inflammation and tumor promotion. It seems unlikely that superoxide anion generation is involved in the mechanism of BrMBA-caused skin tumor promotion.


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