Törmä H, Stenström E, Andersson E, Vahlquist A
Department of Dermatology, University Hospital, Linköping, Sweden.
Skin Pharmacol. 1991;4(4):246-53. doi: 10.1159/000210958.
For unknown reasons, the epidermal concentrations of retinol and its metabolite 3,4-didehydroretinol become characteristically changed during treatment with certain synthetic retinoids. In the present study we investigated [3H]retinol uptake and conversion to 3,4-[3H]didehydroretinol in cultured human skin exposed to six different retinoids. The tissue accumulation of [3H]retinol increased by 50-130% following addition of 1.3 microM of all-trans-retinoic acid, 13-cis-retinoic acid, or 3,4-didehydroretinoic acid (putative metabolites of retinol), and by 13-55% after addition of acitretin, arotenoid Ro 13-7410, or 4-(N-hydroxyphenyl)retinamide. The formation of 3,4-[3H]didehydroretinol was markedly inhibited (minus 80-90%) by the three putative retinol metabolites, moderately inhibited (minus 60-70%) by the aromatic retinoic acid analogues acitretin and arotinoid, and only slightly inhibited (minus 25%) by 4-(N-hydroxyphenyl)retinamide. Addition of citral and ketoconazole, substances known to interfere with the oxidative metabolism of vitamin A, diminished the formation of 3,4-didehydroretinol by 70 and 95%, respectively, but only marginally affected the retinol values. We conclude that the increase in retinol and marked reduction in 3,4-didehydroretinol concentrations in epidermis especially during treatment with 13-cis-retinoic acid are most likely due to diminished conversion of retinol to 3,4-didehydroretinol, but whether or not this reflects feedback inhibition of retinol metabolism or direct inhibition of a specific enzyme remains to be established. Nonetheless, in vitro analysis of 3,4-didehydroretinol biosynthesis appears to be a sensitive means for screening compounds for their ability to interfere with the cutaneous vitamin A metabolism.
出于未知原因，在使用某些合成类视黄醇进行治疗期间，视黄醇及其代谢物3,4 - 二脱氢视黄醇的表皮浓度会发生特征性变化。在本研究中，我们调查了暴露于六种不同类视黄醇的培养人皮肤中[3H]视黄醇的摄取以及向3,4 - [3H]二脱氢视黄醇的转化。添加1.3微摩尔的全反式维甲酸、13 - 顺式维甲酸或3,4 - 二脱氢视黄酸（视黄醇的假定代谢物）后，[3H]视黄醇的组织蓄积增加了50 - 130%，添加阿维A、类胡萝卜素Ro 13 - 7410或4 - (N - 羟基苯基)视黄酰胺后增加了13 - 55%。三种假定的视黄醇代谢物显著抑制（降低80 - 90%）3,4 - [3H]二脱氢视黄醇的形成，芳香族维甲酸类似物阿维A和类胡萝卜素适度抑制（降低60 - 70%），而4 - (N - 羟基苯基)视黄酰胺仅轻微抑制（降低25%）。添加已知会干扰维生素A氧化代谢的柠檬醛和酮康唑，分别使3,4 - 二脱氢视黄醇的形成减少70%和95%，但对视黄醇值的影响很小。我们得出结论，尤其是在使用13 - 顺式维甲酸治疗期间，表皮中视黄醇增加而3,4 - 二脱氢视黄醇浓度显著降低，最可能是由于视黄醇向3,4 - 二脱氢视黄醇的转化减少，但这是否反映了对视黄醇代谢的反馈抑制或对特定酶的直接抑制仍有待确定。尽管如此，对3,4 - 二脱氢视黄醇生物合成的体外分析似乎是筛选化合物干扰皮肤维生素A代谢能力的一种敏感方法。
