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.

中文翻译：

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Epistane是用于娱乐目的的合成代谢类固醇，可通过上调胆汁酸合成（CYP8B1）并与人肝细胞中的核受体串扰，从而导致胆汁淤积症的胆酸结合水平升高。

合成代谢雄激素类固醇是睾丸激素衍生物，健美者用来增加肌肉质量。Epistane（EPI）是一种口服给药的带有2a-3a表硫环的17α-烷基化睾丸激素衍生物。我们确定了四个人，他们在食用EPI后会持续长久的胆汁淤积。表征了三例患者的胆汁酸（BA）概况，以及这种病理学涉及的分子机制。血清BA池从14倍增加到61倍，这主要是由于主要的共轭BA（胆酸（CA）结合物），而次要的BA非常低。在培养的人类肝细胞的体外实验中，EPI引起了糖CA在培养基中的积累。此外，低至0.01μMEPI会上调关键BA合成基因（CYP7A1，增加65％，而CYP8B1，67％）和BA转运蛋白（NTCP，OSTA和BSEP），并下调FGF19。EPI使肝细胞中荧光BA类似物的摄取/积累增加了50-70％。结果也证明，40μMEPI反激活核受体LXR和PXR。更重要的是，0.01μMEPI激活肝细胞中的AR，导致CYP8B1表达增加。在来自人类肝库的样本中，我们证明了男性中AR的表达与CYP8B1正相关。综上所述，我们得出的结论是，EPI可能通过诱导BA合成并促进BA在肝细胞中的蓄积而引起胆汁淤积，至少部分是通过AR激活。我们预计，人体内BA合成酶和转运基因的大表型变异性为EPI诱发的胆汁淤积的特质性质提供了推定的解释。EPI使肝细胞中荧光BA类似物的摄取/积累增加了50-70％。结果也证明，40μMEPI反激活核受体LXR和PXR。更重要的是，0.01μMEPI激活肝细胞中的AR，导致CYP8B1表达增加。在来自人类肝库的样本中，我们证明了男性中AR的表达与CYP8B1正相关。综上所述，我们得出的结论是，EPI可能通过诱导BA合成并促进BA在肝细胞中的蓄积而引起胆汁淤积，至少部分是通过AR激活。我们预计，人体内BA合成酶和转运基因的大表型变异性为EPI诱发的胆汁淤积的特质性质提供了一个假定的解释。EPI使肝细胞中荧光BA类似物的摄取/积累增加了50-70％。结果也证明，40μMEPI反激活核受体LXR和PXR。更重要的是，0.01μMEPI激活肝细胞中的AR，导致CYP8B1表达增加。在来自人类肝库的样本中，我们证明了男性中AR的表达与CYP8B1正相关。综上所述，我们得出的结论是，EPI可能通过诱导BA合成并促进BA在肝细胞中的蓄积而引起胆汁淤积，至少部分是通过AR激活。我们预计，人体内BA合成酶和转运基因的大表型变异性为EPI诱发的胆汁淤积的特质性质提供了推定的解释。