13-cis-retinoic acid competitively inhibits 3 alpha-hydroxysteroid oxidation by retinol dehydrogenase RoDH-4: a mechanism for its anti-androgenic effects in sebaceous glands?
Retinol dehydrogenase-4 (RoDH-4) converts retinol and 13-cis-retinol to corresponding aldehydes in human liver and skin in the presence of NAD(+). RoDH-4 also converts 3 alpha-androstanediol and androsterone into dihydrotestosterone and androstanedione, which may stimulate sebum secretion. This oxidative 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD) activity of RoDH-4 is competitively inhibited by retinol and 13-cis-retinol. Here, we further examine the substrate specificity of RoDH-4 and the inhibition of its 3 alpha-HSD activity by retinoids. Recombinant RoDH-4 oxidized 3,4-didehydroretinol-a major form of vitamin A in the skin-to its corresponding aldehyde. 13-cis-retinoic acid (isotretinoin), 3,4-didehydroretinoic acid, and 3,4-didehydroretinol, but not all-trans-retinoic acid or the synthetic retinoids acitretin and adapalene, were potent competitive inhibitors of the oxidative 3 alpha-HSD activity of RoDH-4, i.e., reduced the formation of dihydrotestosterone and androstandione in vitro. Extrapolated to the in vivo situation, this effect might explain the unique sebosuppressive effect of isotretinoin when treating acne.
Karlsson
Teresa
T
Department of Medical Sciences/Dermatology and Venereology, University Hospital, Uppsala, Sweden.
Vahlquist
Anders
A
Kedishvili
Natalia
N
Törmä
Hans
H
D000429:Alcohol Oxidoreductases / Q000378:metabolism*; D000726:Androgen Antagonists / Q000494:pharmacology*; D000738:Androsterone / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004817:Epidermis / Q000378:metabolism; D006913:Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D007313:Insecta; D015474:Isotretinoin / Q000494:pharmacology*; D007700:Kinetics; D008954:Models, Biological; D010100:Oxygen / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D012627:Sebaceous Glands / Q000187:drug effects*; D012867:Skin / Q000378:metabolism; D013997:Time Factors; D014212:Tretinoin / Q000378:metabolism
D000726:Androgen Antagonists; D011994:Recombinant Proteins; D014212:Tretinoin; D000738:Androsterone; D000429:Alcohol Oxidoreductases; D006913:Hydroxysteroid Dehydrogenases; C113992:trans-retinol dehydrogenase; C022520:retinol dehydrogenase; C035507:3(17)-hydroxysteroid dehydrogenase; D015474:Isotretinoin; D010100:Oxygen