Chen W C, Sass J O, Seltmann H, Nau H, Orfanos C E, Zouboulis C C
Department of Dermatology, University Medical Center Benjamin Franklin, The Free University of Berlin, Germany.
Arch Dermatol Res. 2000 Dec;292(12):612-20. doi: 10.1007/s004030000189.
9-cis-Retinoic acid (9cRA), a geometric isomer of all-trans-retinoic acid (atRA), is an endogenous high-affinity ligand for retinoid X receptors and retinoic acid receptors activating them with high potency. 9,13-di-cis-Retinoic acid (9,13dcRA) has been described as a major plasma metabolite of 9cRA. In this study, the biological activity and the metabolism of 9cRA and 9,13dcRA were investigated and compared with those of atRA in a retinol-free culture system of HaCaT keratinocytes. 9cRA exhibited a slightly weaker activity overall than atRA in inhibiting cell proliferation, inducing cellular retinoic acid binding protein II (CRABP II) mRNA levels and upregulating cytokeratin 19 expression. 9,13dcRA regulated HaCaT keratinocyte activity only at the highest concentration tested (10(-6) M). In cultures of HaCaT keratinocytes with atRA and 9cRA, rapid intracellular accumulation of atRA was observed within 2 h, and atRA levels were higher with atRA treatment than with 9cRA treatment. 9,13dcRA remained relatively stable in the medium with intracellular 9,13dcRA levels below the level of detection. Taken together, 9cRA seems to be slightly less potent than atRA in regulating the biological activity of HaCaT keratinocytes, while its metabolite 9,13dcRA is effectively inactive at biologically relevant concentrations. Our data suggest a prodrug/drug relationship between 9cRA and atRA in human keratinocytes. 9,13dcRA seems to be a weaker prodrug of atRA or an inactive metabolic derivative.
9-顺式维甲酸（9cRA）是全反式维甲酸（atRA）的几何异构体，是一种内源性高亲和力配体，可与维甲酸X受体和维甲酸受体高效结合并激活它们。9,13-二顺式维甲酸（9,13dcRA）被认为是9cRA的主要血浆代谢产物。在本研究中，在无视黄醇的HaCaT角质形成细胞培养系统中，研究并比较了9cRA和9,13dcRA的生物活性及代谢情况，并与atRA进行了对比。在抑制细胞增殖、诱导细胞维甲酸结合蛋白II（CRABP II）mRNA水平以及上调细胞角蛋白19表达方面，9cRA的总体活性略弱于atRA。9,13dcRA仅在最高测试浓度（10⁻⁶ M）时调节HaCaT角质形成细胞活性。在atRA和9cRA处理的HaCaT角质形成细胞培养物中，2小时内观察到atRA在细胞内迅速积累，且atRA处理组的atRA水平高于9cRA处理组。9,13dcRA在培养基中相对稳定，细胞内9,13dcRA水平低于检测限。综上所述，在调节HaCaT角质形成细胞的生物活性方面，9cRA的效力似乎略低于atRA，而其代谢产物9,13dcRA在生物学相关浓度下实际上无活性。我们的数据表明，在人角质形成细胞中，9cRA和atRA之间存在前体药物/药物关系。9,13dcRA似乎是atRA较弱的前体药物或无活性的代谢衍生物。
