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.