The food and fragrance additive citral (3,7-dimethyl-2,6-octadienal) inhibits the oxidation of retinol to retinoic acid in mouse epidermis on local application. This inhibitory property was used to test the hypothesis that oxidation to retinoic acid is rate limiting for the biological activity of vitamin A (retinol) in epithelial tissues. Citral was tested as a modulator of the biological activities of retinol and retinoic acid using two bioassays performed in Skh/hr1 (hairless) mice: (a) the ability to induce epidermal hyperplasia; (b) the ability to inhibit the induction of epidermal ornithine decarboxylase activity by tumor promoters. Citral treatment inhibited the ability of retinol, but not of retinoic acid, to induce epidermal hyperplasia. Similarly, citral treatment decreased the ability of retinol, but not of retinoic acid, to inhibit the induction of epidermal ornithine decarboxylase activity by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate. Although citral had little effect on epidermal ornithine decarboxylase activity when applied alone, it potentiated the induction of ornithine decarboxylase activity by 12-O-tetradecanoylphorbol-13-acetate. The ability of citral to inhibit retinoic acid formation from retinol and the specificity of citral for inhibition of the biological activities of retinol but not retinoic acid are evidence that oxidation to retinoic acid is obligatory for the measured biological activities of retinol. Furthermore, the ability of citral to potentiate the induction of ornithine decarboxylase activity by 12-O-tetradecanoylphorbol-13-acetate suggests that modulation of the retinol oxidation pathway by such agents may enhance susceptibility to tumor promoters.
This research is supported by Awards AR 34638 and CA 47758 from the NIH and by the Veterans Administration. Some of the data in this study were presented at the Annual Meeting of the Society for Investigative Dermatology, Washington, DC, May 1988.