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Inhibition by 2(3)-tert-Butyl-4-hydroxyanisole and Other Antioxidants of Epidermal Ornithine Decarboxylase Activity Induced by 12-O-Tetradecanoylphorbol-13-acetate¹

Departments of Environmental Health Sciences [W. J. K., T. W. K.] and Immunology and Infectious Diseases [J. L. S.], School of Hygiene and Public Health, Johns Hopkins University, Baltimore, Maryland 21205

The relationship between reactive oxygen and/or free radical species and tumor promotion was evaluated by investigating the inhibitory effects of 2(3)-tert-butyl-4-hydroxyanisole (BHA) and other antioxidants on the induction of ornithine decarboxylase (ODC) activity in mouse epidermis by a tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA). Mice maintained on a diet containing 0.75% BHA for 8 days showed a 50% reduction in maximal ODC induction following treatment with TPA when compared to mice fed a control diet. Topical application of BHA (55 µmol) 30 min prior to TPA treatment (17 nmol) elicited an 80% inhibition of promoter-induced ODC activity. BHA was ineffective as an inhibitor when administered either 16 hr before or 2 hr after the promoter. The inhibition by BHA was dose dependent with a dose producing a 50% inhibition of ODC induction of 6 µmol. A structure-activity study with BHA analogues (2-tert-butyl-4-hydroxyanisole, 3-tert-butyl-4-hydroxyanisole, 2-tert-butyl-1,4-dimethoxybenzene, tert-butylhydroquinone, 4-hydroxyanisole, p-hydroquinone, phenol, and 2-tert-butylphenol) showed that hydroxyl and tert-butyl substituents were important determinants of inhibitory activity. A spectrum of other antioxidants were also tested. Butylated hydroxytoluene was nearly equipotent to BHA; -tocopherol, propyl gallate, and disulfiram were all less potent, and L-ascorbate was inactive. None of the antioxidants affected basal ODC activity in non-TPA-treated mice. Collectively, these results demonstrate an early and direct inhibition of TPA-induced ODC activity by lipophilic phenolic antioxidants and suggest a role for reactive oxygen and/or free radical species in tumor promotion.

¹ Financial support was provided by NIH Grants ES07067 and ES00454 and American Cancer Society Grant SIG-3. Preliminary accounts of this work were presented at the 1982 Annual Meeting of the American Association for Cancer Research, Inc. (16).

² To whom requests for reprints should be addressed.

Received 10/20/82. Accepted 3/ 4/83.

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