A comparative study of the induction of epidermal hyperplasia by natural and synthetic retinoids.
Retinoids are potent inducers of epidermal hyperplasia. In the present study the ability to induce epidermal hyperplasia by a variety of retinoids has been compared. Thirteen retinoids and beta-carotene were applied topically in an acetone vehicle to the dorsal skin of hairless mice and the dose-response and time course for the induction of hyperplasia were measured. Peak hyperplasia occurred 4 to 5 days after a single topical dose, and was induced by doses well below those producing gross or histological signs of cutaneous toxicity. The induction of hyperplasia was dose-dependent, the number of epidermal cell layers increasing initially in proportion to the log of the dose and then tending to plateau or, in some cases decrease, after which further increases in dose were associated with the appearance of gross and histological toxicity. The slopes of the initial increasing phase were determined and potencies expressed as the dose producing a 50% increase in the number of epidermal cell layers. All-trans-retinoic acid and its analogs, etretinate and its free acid, (E)-4[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 2-naphthalenyl)-1-propenyl]-benzoic acid (arotinoid) derivatives, retinol and retinal produced an increase in the number of cell layers proportionate to the log of the dose. Decarboxylated (E)-4[2-(5,6,7,8-tetrahydro-5,5,8,8- -tetramethyl-2-naphthalenyl-1-propenyl]-benzoic acid, a cis-locked aryl triene derivative of retinoic acid and beta-carotene were inactive. Similar time courses were observed when retinoids were dosed p.o. The relative potencies of the retinoids in this system show similar trends to those reported for biological activities measured in other in vivo and in vitro assays.
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004817:Epidermis / Q000187:drug effects* / Q000473:pathology; D005260:Female; D006965:Hyperplasia / Q000139:chemically induced; D051379:Mice; D012176:Retinoids / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D013329:Structure-Activity Relationship; D013997:Time Factors
D012176:Retinoids