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

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:

• Ziram
• neurosteroid
• 5α-reductase 1
• 3α-hydroxysteroid dehydrogenase

Acknowledgements

The authors thank T. M. Penning (University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA) for AKR1C14 vector.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This research was supported by Health & Family Planning Commission of Zhejiang Province (11-CX29, 2014C37017, and 2017KY466) and Wenzhou Science & Technology Bureau (2014Y0065).