Reynolds N J, Fisher G J, Griffiths C E, Tavakkol A, Talwar H S, Rowse P E, Hamilton T A, Voorhees J J
Department of Dermatology, University of Michigan, Ann Arbor.
J Pharmacol Exp Ther. 1993 Sep;266(3):1636-42.
Topical all-trans retinoic acid (RA) modulates growth and differentiation of skin and is used in the treatment of various dermatological disorders. RA is metabolized to 4-hydroxy RA, 4-oxo RA and 5,6-epoxy RA, which are believed to be markedly less active than RA. 3,4-didehydroretinoic acid (ddRA) is a metabolite of 3,4-didehydroretinol which is present in skin. ddRA is biologically active and acts as a morphogen. We have determined the relative biological activity of ddRA, 4-hydroxy RA, 4-oxo RA and 5,6-epoxy RA as assessed by three retinoid responsive systems relevant to skin. RA, ddRA, 4-hydroxy RA, 4-oxo RA and 5,6-epoxy RA (10-100 nM) reduced epidermal transglutaminase activity in human keratinocytes to similar extents, and inhibited alpha-melanocyte-stimulating hormone-isobutylmethylxanthine-inducible tyrosinase activity in Cloudman S-91 mouse melanoma cells by 67, 39, 48, 51 and 19%, respectively, at 100 nM. Daily topical application of the retinoids to hairless mouse skin for 4 days resulted in dose-dependent changes in epidermal thickness and global histological score. The relative potencies of RA, ddRA, 4-hydroxy RA, 4-oxo RA and 5,6-epoxy RA, as calculated by parallel line assay, were 1.0, 0.60, 0.34, 0.29 and 0.18, respectively, for epidermal hyperplasia and 1.0, 0.78, 0.23, 0.14 and 0.08, respectively, for global histological score. Interestingly, the compounds exhibited a similar rank order of potency with respect to induction of cellular retinoic acid binding protein-II mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)
外用全反式维甲酸（RA）可调节皮肤的生长和分化，用于治疗多种皮肤病。RA可代谢为4-羟基RA、4-氧代RA和5,6-环氧RA，据信它们的活性明显低于RA。3,4-二脱氢维甲酸（ddRA）是皮肤中存在的3,4-二脱氢视黄醇的代谢产物。ddRA具有生物活性，可作为形态发生原。我们通过与皮肤相关的三种类视黄醇反应系统，测定了ddRA、4-羟基RA、4-氧代RA和5,6-环氧RA的相对生物活性。RA、ddRA、4-羟基RA、4-氧代RA和5,6-环氧RA（10-100 nM）在相似程度上降低了人角质形成细胞中的表皮转谷氨酰胺酶活性，在100 nM时，分别抑制了Cloudman S-91小鼠黑色素瘤细胞中α-黑素细胞刺激激素-异丁基甲基黄嘌呤诱导的酪氨酸酶活性的67%、39%、48%、51%和19%。将类视黄醇每日局部应用于无毛小鼠皮肤4天，导致表皮厚度和整体组织学评分出现剂量依赖性变化。通过平行线分析计算，RA、ddRA、4-羟基RA、4-氧代RA和5,6-环氧RA对于表皮增生的相对效力分别为1.0、0.60、0.34、0.29和0.18，对于整体组织学评分分别为1.0、0.78、0.23、0.14和0.08。有趣的是，这些化合物在诱导细胞视黄酸结合蛋白-II mRNA方面表现出相似的效力等级顺序。（摘要截断于250字）
