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.
D015127:9,10-Dimethyl-1,2-benzanthracene; D000287:Administration, Topical; D000818:Animals; D002273:Carcinogens; D004032:Diet; D005260:Female; D017313:Fenretinide; D007536:Isomerism; D051379:Mice; D008815:Mice, Inbred Strains; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000473:pathology; D013329:Structure-Activity Relationship; D014212:Tretinoin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity*
D002273:Carcinogens; D017313:Fenretinide; D014212:Tretinoin; D015127:9,10-Dimethyl-1,2-benzanthracene