bromochloroacetic-acid and 4-(2-(5-6-7-8-tetrahydro-5-5-8-8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic-acid

Using mouse tail epidermis as a model system we have studied the morphologic and biochemical effects of continuous topical treatment with vitamin A acid. Normal tail epidermis shows a regular pattern of parakeratotic scale regions and orthokeratotic interscale regions which arise postnatally from a uniformly orthokeratinizing neonatal epidermis. Daily treatment of tail epidermis with vitamin A acid for 14 days results in the induction of hyperplasia and the orthokeratotic conversion of the scale regions. The degree of these alterations is dose-dependent and maximally brought about by repetitive 30-microgram doses of the vitamin. To correlate morphologic with biochemical alterations, we have analyzed the keratin patterns of normal and vitamin A acid-treated epidermis by one- and two-dimensional gel electrophoresis. The results indicate that repetitive vitamin A treatment leads to the selective suppression of two postnatally acquired 70 kD and 65 kD type II keratin proteins. Again the minimum repetitive dose required for their complete suppression is 30 micrograms vitamin A acid. Kinetic studies reveal an initial lag phase of 6 days of apparent nonresponsiveness, followed by a 5-day period during which the adult pattern is gradually replaced by the neonatal pattern. Repetitive treatment of tail epidermis with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate leads to a strong hyperplasia; however, it strictly maintains the scale parakeratosis. Under these conditions only the 70 kD keratin subunit is suppressed. This indicates that the suppression of the 70 kD keratin is generally linked to the induction of hyperproliferation, whereas the suppression of the scale-associated 65 kD subunit is due to the metaplastic potency of vitamin A. We provide evidence that this vitamin A-specific in vivo effect can be used to determine the biologic activity of synthetic retinoids relative to vitamin A acid.

Topics: Animals; Benzoates; Electrophoresis, Polyacrylamide Gel; Epidermal Cells; Epidermis; Female; Keratins; Mice; Molecular Weight; Retinoids; Stereoisomerism; Tail; Tetradecanoylphorbol Acetate; Time Factors; Tretinoin