Butylated hydroxyanisole alters rat 5α-reductase and 3α-hydroxysteroid dehydrogenase: Implications for influences of neurosteroidogenesis

Neurosci Lett. 2017 Jul 13;653:132-138. doi: 10.1016/j.neulet.2017.05.034. Epub 2017 May 24.

Abstract

Butylated hydroxyanisole is a synthetic antioxidant. It may affect the function of the nerve system. The objective of the present study is to investigate the direct effects of butylated hydroxyanisole on rat brain neurosteroidogenic 5α-reductase 1 (SRD5A1), 3α-hydroxysteroid dehydrogenase (AKR1C14), and retinol dehydrogenase 2 (RDH2). Rat SRD5A1, AKR1C14, and RDH2 were cloned and expressed in COS1 cells, and the effects of butylated hydroxyanisole on these enzyme activities were measured. Butylated hydroxyanisole inhibited SRD5A1, AKR1C14, and RDH2 with IC50 values of 4.731±0.079μM, 5.753±0.073μM, and over 100μM, respectively. Butylated hydroxyanisole is a competitive inhibitor for both SRD5A1 and AKR1C14. Docking analysis shows that butylated hydroxyanisole binds to the dihydrotestosterone-binding site of AKR1C14. In conclusion, butylated hydroxyanisole is a potent inhibitor of SRD5A1 and AKR1C14, thus reducing the formation of active neurosteroids.

Keywords: 3α-hydroxysteroid dehydrogenase; 5α-reductase 1; Butylated hydroxyanisole; Neurosteroid; Retinol dehydrogenase 2.

MeSH terms

  • 3-Oxo-5-alpha-Steroid 4-Dehydrogenase / metabolism
  • Alcohol Oxidoreductases / antagonists & inhibitors
  • Alcohol Oxidoreductases / metabolism
  • Animals
  • Binding Sites
  • Butylated Hydroxyanisole / administration & dosage*
  • Butylated Hydroxyanisole / pharmacokinetics
  • COS Cells
  • Chlorocebus aethiops
  • Membrane Proteins / antagonists & inhibitors*
  • Membrane Proteins / metabolism
  • Molecular Docking Simulation
  • Oxidoreductases / antagonists & inhibitors*
  • Oxidoreductases / metabolism

Substances

  • Membrane Proteins
  • Butylated Hydroxyanisole
  • Oxidoreductases
  • Alcohol Oxidoreductases
  • retinol dehydrogenase
  • trans-1,2-dihydrobenzene-1,2-diol dehydrogenase
  • 3-Oxo-5-alpha-Steroid 4-Dehydrogenase
  • Srd5a1 protein, rat