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首页> 外文期刊>Archives of Dermatological Research >Both all-trans retinoic acid and cytochrome P450 (CYP26) inhibitors affect the expression of vitamin A metabolizing enzymes and retinoid biomarkers in organotypic epidermis
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Both all-trans retinoic acid and cytochrome P450 (CYP26) inhibitors affect the expression of vitamin A metabolizing enzymes and retinoid biomarkers in organotypic epidermis

机译：全反式维甲酸和细胞色素P450（CYP26）抑制剂均影响器官型表皮中维生素A代谢酶和类维生素A生物标志物的表达

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The biosynthesis of retinoic acid (RA) from retinol is controlled by several enzymes, e.g. dehydrogenases (RalDH2, RoDH-4) and retinol-esterifying enzyme (LRAT), whereas its degradation mainly involves CYP26 enzymes. In keratinocytes, RA activates the nuclear retinoid-receptors inducing the transcription of many genes. Here, we examined the effects of RA and the CYP26 inhibitors, liarozole and talarozole, on retinoid metabolism and RA-regulated genes in organotypic epidermis. RA induced the expression of CYP26 enzymes already after 8 h, whereas LRAT exhibited a later response and peaked at 48 h, indicating a feedback induction of retinol esterification. In line with a reduced biosynthesis of RA from retinol after exogenous RA, the expression of RDH16 reduced 80% in response to exogenous RA. The mRNA expression of RA-regulated genes (KRT2, KRT4, CRABPII and HBEGF) was altered within 24 h after RA exposure. In contrast, the CYP26 inhibitors caused only minor effects, except for a clear-cut induction of CYP26A1 only when combined with minute amounts of exogenous RA. Cellular accumulation of exogenous [3H]RA was higher after talarozole than after liarozole, probably indicating a greater CYP26-inhibitory potency of the former drug. The present study shows that CYP26A1 expression is extremely sensitive to both exogenous RA and increased endogenous RA levels, i.e. due to CYP26 inhibition, and thus an excellent biomarker for retinoid signalling in organotypic epidermis.
机译：由视黄醇的视黄酸（RA）的生物合成受几种酶的控制，例如脱氢酶（RalDH2，RoDH-4）和视黄醇酯化酶（LRAT），而其降解主要涉及CYP26酶。在角质形成细胞中，RA激活核维甲酸受体，从而诱导许多基因的转录。在这里，我们检查了RA和CYP26抑制剂liarozole和talarozole对类器官表皮中类维生素A代谢和RA调控基因的影响。 RA已在8 h后诱导CYP26酶的表达，而LRAT表现出较晚的响应并在48 h达到峰值，表明视黄醇酯化的反馈诱导。与外源性RA后视黄醇的RA生物合成减少相一致，响应于外源性RA，RDH16的表达降低80％。 RA暴露后24小时内，RA调节基因（KRT2，KRT4，CRABPII和HBEGF）的mRNA表达发生改变。相反，CYP26抑制剂仅引起次要作用，只有当与少量外源性RA结合时才明显诱导CYP26A1。他拉唑后，外源[ 3 H] RA的细胞蓄积高于利拉唑后，这可能表明前一种药物对CYP26的抑制作用更大。本研究表明CYP26A1表达对外源RA和内源性RA水平均极为敏感，即由于CYP26抑制，因此是类器官表皮中类维生素A信号传导的极佳生物标志物。

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