Comparative activity of dietary or topical exposure to three retinoids in the promotion of skin tumor induction in mice.

The activity of dietary and topical administration of three retinoids, all-trans-retinoic acid, 13-cis-retinoic acid, and N-(4-hydroxyphenyl)retinamide (4-HPR), as promoters of skin tumor induction in SENCAR mice was studied. When administered as dietary supplements at their maximum tolerated dose levels, all three retinoids promoted tumorigenesis in mice initiated with a single topical dose of 5 micrograms 7,12-dimethylbenz(a)anthracene. Maximal promoting activity was observed with dietary 13-cis-retinoic acid; dietary 4-HPR was significantly less active than was either isomer of retinoic acid. When administered via topical application, all-trans- and 13-cis-retinoic acids both promoted skin tumor induction; 4-HPR did not. HPLC analysis of skin samples from mice receiving dietary 4-HPR showed the parent compound and six metabolites; these metabolites were not found in the skin of mice receiving topical 4-HPR exposure, although 4-HPR itself was present. These data indicate that skin tumor promotion can be induced by systemic administration as well as topical application of the all-trans- and 13-cis-retinoic acids. Substitution of a 4-hydroxyphenylamide terminal group results in a significant reduction in promoting activity. 4-HPR appears to require metabolic activation for tumor promoting activity; this metabolism does not occur in the skin following topical application, but is observed following systemic exposure.