Liu Shiwen, Mao Baiping, Bai Yanfang, Liu Jianpeng, Li Huitao, Li Xiaoheng, Lian Qingquan, Ge Ren-Shan
Department of Anesthesiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang China.
Pharmacology. 2016;97(3-4):126-33. doi: 10.1159/000442711. Epub 2016 Jan 7.
Progesterone and estradiol produced by the human placenta are critical for maintenance of pregnancy and fetal development. In the human placenta, 3β-hydroxysteroid dehydrogenase 1 (HSD3B1) is responsible for the formation of progesterone from pregnenolone and aromatase (CYP19A1) for the production of estradiol from androgen. Insecticide methoxychlor (MXC) and its metabolite hydroxychlor (HPTE) may disrupt the activities of these 2 enzymes. In this study, we investigated the effects of MXC and HPTE on steroid production in human placental JEG-3 cells and on HSD3B1 and CYP19A1 activities. MXC and HPTE inhibited progesterone and estradiol production in JEG-3 cells. MXC and HPTE were potent HSD3B1 inhibitors with the half maximal inhibitory concentration (IC50) values of 2.339 ± 0.096 and 1.918 ± 0.078 μmol/l, respectively. MXC had no inhibition on CYP19A1 at 100 μmol/l, while HPTE was a weak inhibitor with IC50 of 97.16 ± 0.10 μmol/l. When pregnenolone was used to determine the inhibitory mode, MXC and HPTE were found to be competitive inhibitors of HSD3B1. When cofactor NAD+ was used, MXC and HPTE were the noncompetitive inhibitors of HSD3B1. When testosterone was used, HPTE was a mixed inhibitor of CYP19A1. In conclusion, MXC and HPTE are potent inhibitors of human HSD3B1, and HPTE is a weak CYP19A1 inhibitor.
人胎盘产生的孕酮和雌二醇对于维持妊娠及胎儿发育至关重要。在人胎盘中，3β - 羟基类固醇脱氢酶1（HSD3B1）负责将孕烯醇酮转化为孕酮，而芳香化酶（CYP19A1）则负责将雄激素转化为雌二醇。杀虫剂甲氧滴滴涕（MXC）及其代谢产物羟基氯丹（HPTE）可能会干扰这两种酶的活性。在本研究中，我们调查了MXC和HPTE对人胎盘JEG - 3细胞中类固醇生成以及HSD3B1和CYP19A1活性的影响。MXC和HPTE抑制了JEG - 3细胞中孕酮和雌二醇的生成。MXC和HPTE是强效的HSD3B1抑制剂，半数最大抑制浓度（IC50）值分别为2.339±0.096和1.918±0.078μmol/l。100μmol/l的MXC对CYP19A1没有抑制作用，而HPTE是一种弱抑制剂，IC50为97.16±0.10μmol/l。当使用孕烯醇酮来确定抑制模式时，发现MXC和HPTE是HSD3B1的竞争性抑制剂。当使用辅因子NAD⁺时，MXC和HPTE是HSD3B1的非竞争性抑制剂。当使用睾酮时，HPTE是CYP19A1的混合型抑制剂。总之，MXC和HPTE是人类HSD3B1的强效抑制剂，而HPTE是一种弱的CYP19A1抑制剂。
