Ziram inhibits rat neurosteroidogenic 5α-reductase 1 and 3α-hydroxysteroid dehydrogenase

Toxicol Mech Methods. 2018 Jan;28(1):38-44. doi: 10.1080/15376516.2017.1355950.

Abstract

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 IC50 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.

Keywords: 3α-hydroxysteroid dehydrogenase; 5α-reductase 1; Ziram; neurosteroid.

MeSH terms

  • 3-Oxo-5-alpha-Steroid 4-Dehydrogenase / chemistry
  • 3-Oxo-5-alpha-Steroid 4-Dehydrogenase / genetics
  • 3-Oxo-5-alpha-Steroid 4-Dehydrogenase / metabolism
  • Alcohol Oxidoreductases / antagonists & inhibitors
  • Alcohol Oxidoreductases / chemistry
  • Alcohol Oxidoreductases / genetics
  • Alcohol Oxidoreductases / metabolism
  • Aldehyde Reductase / antagonists & inhibitors*
  • Aldehyde Reductase / chemistry
  • Aldehyde Reductase / genetics
  • Aldehyde Reductase / metabolism
  • Animals
  • Binding Sites
  • Binding, Competitive
  • COS Cells
  • Chlorocebus aethiops
  • Fungicides, Industrial / chemistry
  • Fungicides, Industrial / metabolism
  • Fungicides, Industrial / toxicity*
  • Membrane Proteins / antagonists & inhibitors*
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Molecular Docking Simulation
  • Neurotransmitter Agents / biosynthesis*
  • Protein Binding
  • Protein Conformation
  • Risk Assessment
  • Structure-Activity Relationship
  • Transfection
  • Ziram / chemistry
  • Ziram / metabolism
  • Ziram / toxicity*

Substances

  • Fungicides, Industrial
  • Membrane Proteins
  • Neurotransmitter Agents
  • Ziram
  • Alcohol Oxidoreductases
  • retinol dehydrogenase
  • Aldehyde Reductase
  • Akr1c14 protein, rat
  • 3-Oxo-5-alpha-Steroid 4-Dehydrogenase
  • Srd5a1 protein, rat