Epistane, an anabolic steroid used for recreational purposes, causes cholestasis with elevated levels of cholic acid conjugates, by upregulating bile acid synthesis (CYP8B1) and cross-talking with nuclear receptors in human hepatocytes

Epistane, an anabolic steroid used for recreational purposes, causes cholestasis with elevated levels of cholic acid conjugates, by upregulating bile acid synthesis (CYP8B1) and cross-talking with nuclear receptors in human hepatocytes / Petar D. Petrov, Leonor Fernández-Murga, Isabel Conde, Teresa Martínez-Sena, Carla Guzmán, José Vicente Castell, Ramiro Jover. -  (Archives of Toxicology 94 (2020) 2 (February) p. 589-607)

  • PMID: 31894354
  • DOI: 10.1007/s00204-019-02643-y


Abstract

Anabolic-androgenic steroids are testosterone derivatives, used by body-builders to increase muscle mass. Epistane (EPI) is an orally administered 17α-alkylated testosterone derivative with 2a-3a epithio ring. We identified four individuals who, after EPI consumption, developed long-lasting cholestasis. The bile acid (BA) profile of three patients was characterized, as well the molecular mechanisms involved in this pathology. The serum BA pool was increased from 14 to 61-fold, basically on account of primary conjugated BA (cholic acid (CA) conjugates), whereas secondary BA were very low. In in vitro experiments with cultured human hepatocytes, EPI caused the accumulation of glycoCA in the medium. Moreover, as low as 0.01 μM EPI upregulated the expression of key BA synthesis genes (CYP7A1, by 65% and CYP8B1, by 67%) and BA transporters (NTCP, OSTA and BSEP), and downregulated FGF19. EPI increased the uptake/accumulation of a fluorescent BA analogue in hepatocytes by 50-70%. Results also evidenced, that 40 μM EPI trans-activated the nuclear receptors LXR and PXR. More importantly, 0.01 μM EPI activated AR in hepatocytes, leading to an increase in the expression of CYP8B1. In samples from a human liver bank, we proved that the expression of AR was positively correlated with that of CYP8B1 in men. Taken together, we conclude that EPI could cause cholestasis by inducing BA synthesis and favouring BA accumulation in hepatocytes, at least in part by AR activation. We anticipate that the large phenotypic variability of BA synthesis enzymes and transport genes in man provide a putative explanation for the idiosyncratic nature of EPI-induced cholestasis.

Parameters

Science
Study
Date
1 January 2020
People
Castell, José Vicente
Conde, Isabel
Fernández-Murga, Leonor
Guzmán, Carla
Jover, Ramiro
Martínez-Sena, Teresa
Petrov, Petar D.
Country
Spain
Language
English
Other organisations
Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas (CIBERehd) - Biomedical Research Networking Center in Hepatic and Digestive Diseases
Hospital Uni­versitari i Politècnic La Fe - University and Polytechnic La Fe Hospital
Instituto de Investigación Sanitaria La Fe (IIS La Fe) - Health Research Institute Hospital La Fe
Universitat de València (UV) - University of Valencia
Doping classes
S1. Anabolic Agents
Medical terms
Health effects
Document category
Abstract
Date generated
10 February 2021
Date of last modification
11 February 2021
Category
  • Legal Source
  • Education
  • Science
  • Statistics
  • History
Country & language
  • Country
  • Language
Other filters
  • ADRV
  • Legal Terms
  • Sport/IFs
  • Other organisations
  • Laboratories
  • Analytical aspects
  • Doping classes
  • Substances
  • Medical terms
  • Various
  • Version
  • Document category
  • Document type
Publication period
Origin