Lack of biological activity of physiological metabolites of all-trans-retinoic acid on vaginal epithelial differentiation.
It has been of interest to determine whether the metabolites of physiological doses of retinoic acid represent active forms of vitamin A. Previous work (Biochem. J. 206, 33-41, 1982) studied the metabolites produced from 2-micrograms doses of all-trans-retinoic acid in the vitamin A-deficient rat. Four major metabolites common to all of the tissues studied were discovered. In the present work, three of these metabolites are isolated from vitamin A-deficient rats given physiological doses (5 micrograms) of all-trans-retinoic acid and from vitamin A-sufficient rats given high doses (1 mg) of all-trans-retinoic acid. Cochromatography on anion-exchange and reverse-phase high-performance liquid chromatography showed that metabolites resulting from high doses of retinoic acid contained the metabolites generated from physiological doses of retinoic acid. Quantities of these metabolites were isolated, purified, and tested for their epithelial-differentiating activity in the vitamin A-deficient rat vagina. The metabolites were inactive at all dose levels tested. These metabolites have less than 10% the biological activity of all-trans-retinoic acid. Therefore, these metabolites appear to be products of the inactivation of all-trans-retinoic acid. Based upon these and previous data, it seems likely that all-trans-retinoic acid or its beta-glucuronide derivative is the most likely active form of vitamin A in the maintenance of normal epithelial differentiation.
Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison 53706.
D P
DP
Silva
C R
CR
Valliere
H F
HF
DeLuca
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells; D005260:Female; D007536:Isomerism; D051381:Rats; D011919:Rats, Inbred Strains; D014212:Tretinoin / Q000378:metabolism* / Q000494:pharmacology; D014621:Vagina / Q000166:cytology*
D014212:Tretinoin