Potent inhibitors of equine steroid isomerase EcaGST A3-3.

Helena Lindström,Bengt Mannervik,Aslam M A Mazari,Israel Silman,Yaman Musdal

doi:10.1371/journal.pone.0214160

Abstract

Equine glutathione transferase A3-3 (EcaGST A3-3) belongs to the superfamily of detoxication enzymes found in all higher organisms. However, it is also the most efficient steroid double-bond isomerase known in mammals. Equus ferus caballus shares the steroidogenic pathway with Homo sapiens, which makes the horse a suitable animal model for investigations of human steroidogenesis. Inhibition of the enzyme has potential for treatment of steroid-hormone-dependent disorders. Screening of a library of FDA-approved drugs identified 16 out of 1040 compounds, which at 10 μM concentration afforded at least 50% inhibition of EcaGST A3-3. The most potent inhibitors, anthralin, sennoside A, tannic acid, and ethacrynic acid, were characterized by IC50 values in the submicromolar range when assayed with the natural substrate Δ5-androstene-3,17-dione.

Highlights

Steroid hormones are involved in a plethora of physiological processes in mammals, ranging from regulation of blood pressure to reproduction [1]
Progesterone is a sex steroid hormone contributing to embryogenesis and maintaining pregnancy, it plays an important role as an intermediate in metabolic pathways to other endogenous steroids [2]
The chemical compound library was screened for inhibitory effects on EcaGST A3-3 activity using the universal GST substrate 1-chloro-2, 4-dinitrobenzene (CDNB)

Summary

Introduction

Steroid hormones are involved in a plethora of physiological processes in mammals, ranging from regulation of blood pressure to reproduction [1]. Testosterone primarily exerts androgenic and anabolic effects in males [3]. These steroid hormones are mainly produced in testis, ovary, adrenal gland and placenta. Some steroid hormones and their derivatives are active in the nervous system where they are implicated in a variety of diverse physiological and pathophysiological conditions such as cognition, aggression, reproductive behavior, ageing, Alzheimer’s disease, Parkinson’s disease, and brain injury [4,5,6]. Steroid hormones synthesized in the brain and the nervous system are called “neurosteroids”, even though their chemical structures are identical to those of the cognate compounds produced in other tissues

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