Törmä H, Rollman O, Binderup L, Michaelsson G
Department of Dermatology, University Hospital, Uppsala, Sweden.
J Investig Dermatol Symp Proc. 1996 Apr;1(1):49-53.
Human epidermis utilizes retinol as precursor for local production of a range of bioactive vitamin A metabolites including 3,4-didehydroretinol, retinoic acid, and 3,4-didehydroretinoic acid. These endogenously formed retinoids bind to nuclear retinoic acid receptors (RARs), thereby altering gene transcription. Because 9-cis-retinoic acid receptors (RXRs) form heterodimers both with RARs and the vitamin D3 receptor (VDR), it is plausible that vitamin D3 may affect retinol metabolism if altered transcription is involved in the regulation of vitamin A-metabolizing enzymes. To investigate the potential effect of vitamin D on retinol metabolism in human skin keratinocytes, HaCaT cells were preincubated with various vitamin D3-analogs at 10(-7)M for 24 h followed by the addition of [3H]retinol for another 24 h period. The uptake and metabolism of the radioactive tracer was monitored by HPLC-radiochromatography. It was found that all synthetic vitamin D-analogs tested (MC903, KH1060, EB1089, and EB1213) reduced the amount of cell-associated [3H]retinoid activity by 35-50% as compared to the vehicle. More specifically, the appearance of the parent substrate and two of its main metabolites, e.g., 3,4-didehydroretinol (ddROH) and 3,4-didehydroretinoic acid (ddRA), was inhibited by the synthetic vitamin D-analogs. The effects on retinol metabolism were not potentiated by coincubation of cells with vitamin D-analogs plus retinoic acid (RA) or 9-cis-RA. This study demonstrates that synthetic vitamin D3 interferes with both the uptake and the metabolism of retinol by human epidermal keratinocytes. Whether the effects are due to direct inhibition of cellular retinol uptake and metabolism or involve VDR-mediated transcriptional alteration of vitamin A metabolizing enzymes remains to be clarified.
人类表皮利用视黄醇作为前体，在局部生成一系列具有生物活性的维生素A代谢产物，包括3,4-二脱氢视黄醇、视黄酸和3,4-二脱氢视黄酸。这些内源性生成的类视黄醇与核视黄酸受体（RARs）结合，从而改变基因转录。由于9-顺式视黄酸受体（RXRs）既能与RARs形成异源二聚体，也能与维生素D3受体（VDR）形成异源二聚体，因此，如果转录改变参与了维生素A代谢酶的调节，那么维生素D3可能会影响视黄醇代谢。为了研究维生素D对人皮肤角质形成细胞视黄醇代谢的潜在影响，将HaCaT细胞与10(-7)M的各种维生素D3类似物预孵育24小时，然后再加入[3H]视黄醇继续孵育24小时。通过HPLC-放射色谱法监测放射性示踪剂的摄取和代谢。结果发现，与载体相比，所有测试的合成维生素D类似物（MC903、KH1060、EB1089和EB1213）都使细胞相关的[3H]类视黄醇活性降低了35-50%。更具体地说，合成维生素D类似物抑制了母体底物及其两种主要代谢产物（即3,4-二脱氢视黄醇（ddROH）和3,4-二脱氢视黄酸（ddRA））的出现。细胞与维生素D类似物加视黄酸（RA）或9-顺式视黄酸（9-cis-RA）共同孵育，对视黄醇代谢的影响并未增强。这项研究表明，合成维生素D3会干扰人表皮角质形成细胞对视黄醇的摄取和代谢。这些影响是由于直接抑制细胞对视黄醇的摄取和代谢，还是涉及VDR介导的维生素A代谢酶转录改变，仍有待阐明。
