Kang S, Duell E A, Kim K J, Voorhees J J
Department of Dermatology, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0528, U.S.A.
J Invest Dermatol. 1996 Aug;107(2):183-7. doi: 10.1111/1523-1747.ep12329579.
Metabolic inactivation of all-trans retinoic acid to 4-hydroxy retinoic acid occurs via a cytochrome P-450 enzyme. We investigated the effects of liarozole on the retinoic acid 4-hydroxylase activity of human epidermis and its ability to modify in vivo human skin responses to retinoic acid and all-trans retinol. Retinoic acid 4-hydroxylase activity induced in vivo by 4 d treatment with retinoic acid (0.1%) was inhibited in vitro by liarozole in a concentration-dependent manner. Comparable micromolar concentrations of liarozole were extracted from stratum corneum-free epidermis treated with 3% liarozole. Retinoic acid levels in liarozole-treated skin increased to 19 +/- 5 ng/g wet wt (mean +/- SEM, p < 0.002, n = 17) at 18 h and to 6 +/- 2 ng/g wet wt (p = 0.38, n = 17) at 48 h as compared to vehicle (not detectable). At 48 h, retinoic acid 4-hydroxylase activity was induced 9-fold over vehicle (p < 0.03, n = 8). At 96 h, no significant erythema or increased epidermal thickness was found when either retinoic acid (0.001%), all-trans retinol (0.0250%), or liarozole (3%) was applied individually, but when 0.001% retinoic acid and 3% liarozole were applied together, both erythema and increased epidermal thickness occurred. In contrast, 0.025% all-trans retinol and 3% liarozole together caused increased epidermal thickness but no erythema. These data demonstrate that, at doses used here, liarozole, although an effective inhibitor of retinoic acid 4-hydroxylase, cannot function alone like a retinoid in vivo, probably because of retinoic acid 4-hydroxylase induction. In the presence of a low dose retinoic acid or all-trans retinol, however, liarozole can amplify human skin responses to each retinoid in a manner characteristic of the retinoid at a higher dose (erythema and hyperplasia with retinoic acid; no erythema but hyperplasia with all-trans retinol).
全反式维甲酸通过细胞色素P-450酶代谢失活为4-羟基维甲酸。我们研究了来曲唑对人表皮维甲酸4-羟化酶活性的影响及其改变人皮肤对维甲酸和全反式视黄醇体内反应的能力。用维甲酸（0.1%）处理4天在体内诱导的维甲酸4-羟化酶活性，在体外被来曲唑以浓度依赖的方式抑制。用3%来曲唑处理的无角质层表皮中可提取出相当微摩尔浓度的来曲唑。与赋形剂（未检测到）相比，来曲唑处理的皮肤中维甲酸水平在18小时时增加到19±5 ng/g湿重（平均值±标准误，p<0.002，n = 17），在48小时时增加到6±2 ng/g湿重（p = 0.38，n = 17）。在48小时时，维甲酸4-羟化酶活性比赋形剂诱导了9倍（p<0.03，n = 8）。在96小时时，单独应用维甲酸（0.001%）、全反式视黄醇（0.0250%）或来曲唑（3%）时，未发现明显的红斑或表皮厚度增加，但当同时应用0.001%维甲酸和3%来曲唑时，出现了红斑和表皮厚度增加。相比之下，0.025%全反式视黄醇和3%来曲唑一起导致表皮厚度增加但无红斑。这些数据表明，在此处使用的剂量下，来曲唑虽然是维甲酸4-羟化酶的有效抑制剂，但在体内不能像类维生素A那样单独发挥作用，可能是由于维甲酸4-羟化酶的诱导。然而，在低剂量维甲酸或全反式视黄醇存在的情况下，来曲唑可以以更高剂量类维生素A特有的方式放大人类皮肤对每种类维生素A的反应（维甲酸引起红斑和增生；全反式视黄醇无红斑但有增生）。
