Zhu S J, Li Y, Li H, Wang Y L, Xiao Z J, Vihko P, Piao Y S
State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 19 Zhong Guan Cun Road, Beijing 100080, China.
J Endocrinol. 2002 Jan;172(1):31-43. doi: 10.1677/joe.0.1720031.
The biosynthesis of 17beta-estradiol (E(2)) in human placenta involves the actions of aromatase and 17beta-hydroxysteroid dehydrogenase type 1 (17HSD1). Aromatase, an enzyme complex comprised of P450aromatase (P450arom) and NADH-cytochrome P450 reductase, converts androgens to estrogens, whereas 17HSD1 catalyzes the reduction of estrone to E(2). In the present study, the effects of retinoic acids (RAs) on P450arom and 17HSD1 expression in placental cells were investigated. Treatment with all-trans-RA (at-RA) or 9cis-RA increased E(2) production in JEG-3 choriocarcinoma cells and cytotrophoblast (CTB) cells isolated from normal early placentas. Meanwhile, the activity of aromatase and expression of P450arom mRNA were induced by at-RA in JEG-3 cells. Northern blot analysis showed that the effect on P450arom mRNA expression occurs in a dose- and time-dependent fashion. Similar to at-RA and 9cis-RA, Ro40-6055, the retinoic acid receptor alpha (RARalpha)-selective activator, increased the expression of P450arom and 17HSD1 mRNA in JEG-3 cells. On the other hand, Ro41-5253 (Ro41), the RARalpha-selective antagonist, blocked the stimulatory effect of RAs on P450arom expression. Surprisingly, Ro41 induced the activity and mRNA expression of 17HSD1 in JEG-3 cells, which is in contrast to the expected inhibitory effect and, moreover, remarkably potentiated the induction by at-RA and 9cis-RA. However, reporter gene analysis revealed that the influence of Ro41 on the transcription of the HSD17B1 gene, which encodes 17HSD1, is considerably milder in JEG-3 cells, and it only additively enhanced the effect of at-RA. Finally, it was found that at-RA and 9cis-RA increased the expression of P450arom and 17HSD1 mRNA in CTB cells, but to a lesser extent. The data suggest that RAs may play a role in promoting the biosynthesis of E(2 )in the placenta. In addition, Ro41 has divergent effects on gene expression in JEG-3 cells.
人胎盘中17β-雌二醇（E₂）的生物合成涉及芳香化酶和1型17β-羟基类固醇脱氢酶（17HSD1）的作用。芳香化酶是一种由细胞色素P450芳香化酶（P450arom）和NADH-细胞色素P450还原酶组成的酶复合物，可将雄激素转化为雌激素，而17HSD1催化雌酮还原为E₂。在本研究中，研究了视黄酸（RAs）对胎盘细胞中P450arom和17HSD1表达的影响。用全反式视黄酸（at-RA）或9-顺式视黄酸（9cis-RA）处理可增加JEG-3绒毛膜癌细胞和从正常早期胎盘中分离的细胞滋养层（CTB）细胞中E₂的产生。同时，at-RA在JEG-3细胞中诱导了芳香化酶的活性和P450arom mRNA的表达。Northern印迹分析表明，对P450arom mRNA表达产生的影响呈剂量和时间依赖性。与at-RA和9cis-RA类似，视黄酸受体α（RARα）选择性激活剂Ro40-6055增加了JEG-3细胞中P450arom和17HSD1 mRNA的表达。另一方面，RARα选择性拮抗剂Ro41-5253（Ro41）阻断了RAs对P450arom表达的刺激作用。令人惊讶的是，Ro41诱导了JEG-3细胞中17HSD1的活性和mRNA表达，这与预期的抑制作用相反，而且显著增强了at-RA和9cis-RA的诱导作用。然而，报告基因分析显示，Ro41对编码17HSD1的HSD17B1基因转录的影响在JEG-3细胞中相当轻微，它只是相加地增强了at-RA的作用。最后，发现at-RA和9cis-RA增加了CTB细胞中P450arom和17HSD1 mRNA的表达，但程度较小。数据表明，RAs可能在促进胎盘中E₂的生物合成中发挥作用。此外，Ro41对JEG-3细胞中的基因表达有不同的影响。
