Ribavirin has been widely used for antiviral therapy. Unfortunately, ribavirin-induced anemia is often a cause of limiting or interrupting treatment. Our team has observed that dehydroepiandrosterone (DHEA) has a protective effect against in vitro and in vivo ribavirin-induced hemolysis. The aim of this study was to better understand this effect as well as the underlying mechanism(s).

DHEA was able to reduce in vitro intraerythrocytic ATP depletion induced by ribavirin. Only 1% of ATP remained after incubation with ribavirin (2 mM) at 37 °C for 24 h vs. 37% if DHEA (200 μM) was added (p < 0.01). DHEA also helped erythrocytes conserve their size, with a shrinkage of only 10% vs 40% at 24 h with ribavirin alone (p < 0.01), and reduced phosphatidylserine exposure at the outer membrane, i.e. 27% vs 40% at 48 h, (p < 0.05). DHEA also inhibits ribavirin-induced hemolysis, i.e. 34% vs 46.5% at 72 h (p < 0.01).

DHEA is an inhibitor of glucose-6-phosphate dehydrogenase (G6PD), a key enzyme in the hexose monophosphate shunt connected to the glycolytic pathway which is the only energy supplier of the red blood cell in the form of ATP. We have confirmed this inhibitory effect in the presence of ribavirin. All these observations suggest that ribavirin-induced hemolysis was initiated by ATP depletion, and that the inhibitory effect of DHEA on G6PD was able to rescue enough ATP to limit this hemolysis. This mechanism could be important for improving the therapeutic management of patients treated with ribavirin.

利巴韦林已被广泛用于抗病毒治疗。不幸的是，利巴韦林引起的贫血通常是限制或中断治疗的原因。我们的小组观察到，脱氢表雄酮（DHEA）对体外和体内利巴韦林诱导的溶血具有保护作用。这项研究的目的是更好地了解这种影响以及潜在的机制。

DHEA能够减少利巴韦林诱导的体外红细胞内ATP消耗。与利巴韦林（2 mM）在37°C下孵育24小时后，仅保留了1％的ATP，而如果添加了DHEA（200μM），则仅保留了37％（p  <0.01）。DHEA还有助于红细胞保持其大小，仅使用利巴韦林时24小时收缩率仅为10％对40％（p  <0.01），并且减少了外膜磷脂酰丝氨酸的暴露，即48小时时27％对40％（（p  ＜0.05）。DHEA还抑制了利巴韦林诱导的溶血，即在72小时时分别为34％和46.5％（p  <0.01）。

DHEA是6-磷酸葡萄糖脱氢酶（G6PD）的抑制剂，G6-PD是己糖单磷酸旁路中与糖酵解途径相连的关键酶，糖酵解途径是ATP形式的红细胞的唯一能量供应者。我们已经证实在存在利巴韦林的情况下具有这种抑制作用。所有这些观察结果表明，利巴韦林诱导的溶血是由ATP耗竭引起的，并且DHEA对G6PD的抑制作用能够挽救足够的ATP以限制这种溶血。该机制对于改善用利巴韦林治疗的患者的治疗管理可能是重要的。