Laboratoire de Virologie EA4294, Université de Picardie Jules Verne, Centre Hospitalier Universitaire, 80054, Amiens, France.
Laboratoire d'Hématologie EA4666, Université de Picardie Jules Verne, Centre Hospitalier Universitaire, 80054, Amiens, France.
Antiviral Res. 2017 Oct;146:153-160. doi: 10.1016/j.antiviral.2017.09.002. Epub 2017 Sep 8.
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.
利巴韦林被广泛用于抗病毒治疗。不幸的是，利巴韦林引起的贫血常常是限制或中断治疗的原因。我们的团队观察到脱氢表雄酮（DHEA）对体外和体内利巴韦林诱导的溶血具有保护作用。本研究旨在更好地了解这种作用及其潜在机制。DHEA 能够减少利巴韦林诱导的体外红细胞内 ATP 耗竭。与加入 DHEA（200μM）时相比，在 37°C 孵育 24 小时后，利巴韦林（2mM）仅残留 1%的 ATP（p<0.01）。DHEA 还有助于红细胞保持其大小，单独使用利巴韦林时 24 小时后收缩仅为 10%，而收缩为 40%（p<0.01），并且减少了外膜上的磷脂酰丝氨酸暴露，即 48 小时时为 27%，而 40%（p<0.05）。DHEA 还抑制利巴韦林诱导的溶血，即 72 小时时为 34%，而 46.5%（p<0.01）。DHEA 是葡萄糖-6-磷酸脱氢酶（G6PD）的抑制剂，G6PD 是连接糖酵解途径的己糖单磷酸途径的关键酶，是红细胞以 ATP 形式提供的唯一能量来源。我们在存在利巴韦林的情况下证实了这种抑制作用。所有这些观察结果表明，利巴韦林诱导的溶血是由 ATP 耗竭引发的，而 DHEA 对 G6PD 的抑制作用能够挽救足够的 ATP 来限制这种溶血。这种机制对于改善接受利巴韦林治疗的患者的治疗管理可能很重要。
