Duell E A, Kang S, Voorhees J J
Department of Dermatology, University of Michigan Medical School, Ann Arbor 48109-0528, USA.
J Invest Dermatol. 1996 Feb;106(2):316-20. doi: 10.1111/1523-1747.ep12342972.
Application of all-trans retinoic acid to human skin for 4 d under occlusion produces a marked increase in retinoic acid 4-hydroxylase activity. In this study, the possible induction of other hydroxylase in response to 9-cis and 13-cis retinoic acid application to adult human skin in vivo was determined. Application of 0.1% all-trans, 0.1% 9-cis, and 0.1% 13-cis retinoic acid to human skin for 2 d resulted in induction of only all-trans retinoic acid 4-hydroxylase activity. The 4-hydroxylase activity in microsomes from the treated tissue ranged from 838 +/- 46 to 531 +/- 59 pg of 4- hydroxy all-trans retinoic acid formed/min/mg protein (n=6). These same preparations were unable to use 9-cis or 13-cis retinoic acid as substrate for the hydroxylation reaction. Extraction of the retinoic acid isomers from epidermis 48 h after application of 0.1% solution of each isomer yielded significant amounts of all-trans retinoic acid (36-72%) regardless of the isomer applied. The all-trans isomer produced by isomerization of both 9-cis and 13-cis retinoic acids is the likely inducer of the 4-hydroxylase. All-trans retinol and all-trans retinal were unable to compete with all-trans retinoic acid as substrate for 4-hydroxylase enzyme. The 4-hydroxylase induced in response to pharmacological doses of retinoic acids is specific for the all-trans isomer. The inability of 9-cis or 13-cis retinoic acid to induce their own hydroxylation and inactivation or act as substrate for the 4-hydroxylase in skin may have considerable implications in light of the clinical use of retinoids in the treatment of various diseases including cancers.
在封闭条件下，将全反式维甲酸应用于人体皮肤4天会使维甲酸4 - 羟化酶活性显著增加。在本研究中，测定了在体内将9 - 顺式和13 - 顺式维甲酸应用于成人人体皮肤后，是否可能诱导其他羟化酶。将0.1%的全反式、0.1%的9 - 顺式和0.1%的13 - 顺式维甲酸应用于人体皮肤2天，结果仅诱导了全反式维甲酸4 - 羟化酶活性。处理过的组织微粒体中的4 - 羟化酶活性范围为每分钟每毫克蛋白质形成838±46至531±59皮克的4 - 羟基全反式维甲酸（n = 6）。这些相同的制剂不能将9 - 顺式或13 - 顺式维甲酸用作羟化反应的底物。在应用每种异构体的0.1%溶液48小时后，从表皮中提取维甲酸异构体，无论应用何种异构体，均产生了大量的全反式维甲酸（36 - 72%）。由9 - 顺式和13 - 顺式维甲酸异构化产生的全反式异构体可能是4 - 羟化酶的诱导剂。全反式视黄醇和全反式视黄醛不能与全反式维甲酸竞争作为4 - 羟化酶的底物。响应药理剂量的维甲酸诱导的4 - 羟化酶对全反式异构体具有特异性。鉴于维甲酸在包括癌症在内的各种疾病治疗中的临床应用，9 - 顺式或13 - 顺式维甲酸不能诱导自身羟化和失活或作为皮肤中4 - 羟化酶的底物可能具有重要意义。
