a Department of Anesthesiology , The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University , Wenzhou , Zhejiang , People's Republic of China.
b Department of Anesthesia , Hangzhou Hospital Affiliated to Nanjing Medical University, Hangzhou First People's Hospital , Hangzhou , People's Republic of China.
Toxicol Mech Methods. 2018 Jan;28(1):38-44. doi: 10.1080/15376516.2017.1355950.
The neurotoxicity of ziram is largely unknown. In this study, we investigated the direct inhibitions of ziram on rat neurosteroid synthetic and metabolizing enzymes, 5α-reductase 1 (SRD5A1), 3α-hydroxysteroid dehydrogenase (AKR1C14), and retinol dehydrogenase 2 (RDH2). Rat SRD5A1, AKR1C14, and RDH2 were cloned and transiently expressed in COS1 cells, and the effects of ziram on these enzymes were measured. Ziram inhibited rat SRD5A1 and AKR1C14 with IC values of 1.556 ± 0.078 and 1.017 ± 0.072 μM, respectively, when 1000 nM steroid substrates were used. Ziram weakly inhibited RDH2 at 100 μM, when androstanediol (1000 nM) was used. Ziram competitively inhibited SRD5A1 and non-competitively inhibited AKR1C14 when steroid substrates were used. Docking study showed that ziram bound to NADPH-binding pocket of AKR1C14. In conclusion, our results demonstrated that ziram inhibited SRD5A1 and AKR1C14 activities, thus possibly interfering with neurosteroid production in rats.
有关锌尘的神经毒性在很大程度上尚未可知。在本研究中，我们研究了锌尘对大鼠神经甾体合成和代谢酶（5α-还原酶 1（SRD5A1）、3α-羟甾脱氢酶（AKR1C14）和视黄醇脱氢酶 2（RDH2））的直接抑制作用。我们克隆并瞬时表达了大鼠 SRD5A1、AKR1C14 和 RDH2 于 COS1 细胞中，并测量了锌尘对这些酶的影响。当使用 1000nM 甾体底物时，锌尘对大鼠 SRD5A1 和 AKR1C14 的抑制 IC 值分别为 1.556±0.078 和 1.017±0.072μM。当使用 100μM 锌尘和 1000nM 雄烷二醇时，其对 RDH2 的抑制作用较弱。当使用甾体底物时，锌尘竞争性抑制 SRD5A1，非竞争性抑制 AKR1C14。对接研究表明，锌尘与 AKR1C14 的 NADPH 结合口袋结合。综上所述，我们的研究结果表明，锌尘抑制了 SRD5A1 和 AKR1C14 的活性，从而可能干扰了大鼠的神经甾体生成。
