A Naphthoquinone Derivative Can Induce Anemia through Phosphatidylserine Exposure-Mediated Erythrophagocytosis
A Naphthoquinone Derivative Can Induce Anemia through Phosphatidylserine Exposure-Mediated Erythrophagocytosis
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DOI：
10.1124/jpet.109.164608
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发表时间：
2010-05-01
影响因子：
3.5
通讯作者：
Chung, Jin-Ho
中科院分区：
文献类型：
--
作者：
Noh, Ji-Yoon;Park, Jong-Sook;Chung, Jin-Ho
萘醌衍生物β -拉帕酮（β L; 3,4-二氢-2,2-二甲基- 2h -萘酚[1,2-b]吡喃-5,6-二酮）因其对多种疾病的有效治疗作用而受到广泛关注。然而，在临床前安全性评估中，大鼠反复口服β L诱导贫血，即红细胞计数显著降低。在这项研究中，为了阐明β - L诱导贫血的机制，我们在体外和大鼠体内研究了β - L对红细胞的影响。β L不诱导红细胞溶血，表明β L相关性贫血不涉及直接血液毒性。与此同时，β l显著增加了促红细胞吞噬的重要因子磷脂酰丝氨酸（PS）暴露，使其随球型改变和微泡生成而增加。对红细胞的PS暴露是由于β l诱导的活性氧的产生和随后的还原性谷胱甘肽和蛋白硫醇的消耗，最终导致磷脂转位酶活性的改变，即翻转酶的抑制和超燃酶的激活。值得注意的是，巨噬细胞与β - l处理的红细胞在体外共孵育显示红细胞吞噬能力增加，这表明β - l诱导的PS暴露可以促进巨噬细胞清除红细胞。与这些体外结果很好地一致，大鼠口服β L后，观察到PS暴露增加和谷胱甘肽的消耗，同时红细胞的脾隔离增强。总之，这些结果表明β - l诱导的贫血可能通过PS暴露和随后的红细胞吞噬介导，为药物性贫血提供了新的见解。
A naphthoquinone derivative, beta-lapachone (beta L; 3,4-dihydro-2,2- dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione), is receiving huge attention for its potent therapeutic effects against various diseases. However, during the preclinical safety evaluation, repeated oral treatment of beta L in rats induced anemia, i.e., a significantly decreased erythrocyte count. In this study, in an effort to elucidate the mechanism underlying the beta L-induced anemia, we investigated the effects of beta L on erythrocytes with freshly isolated human erythrocytes in vitro and rat in vivo. beta L did not induce erythrocyte hemolysis, indicating that direct hemotoxicity was not involved in beta L-associated anemia. Meanwhile, phosphatidylserine (PS) exposure along with spherocytic shape change and microvesicle generation, important factors in the facilitation of erythrophagocytosis, were increased significantly by beta L. The PS exposure on erythrocytes was from beta L-induced reactive oxygen species generation and subsequent depletion of reduced glutathione and protein thiol, which culminated in the modified activities of phospholipid translocases, i.e., inhibition of flippase and activation of scramblase. It is important to note that coincubation of macrophage with beta L-treated erythrocyte in vitro showed increased erythrophagocytosis, demonstrating that the removal of erythrocyte by macrophage can be facilitated by beta L-induced PS exposure. In good accordance with these in vitro results, after oral administration of beta L in rats, increased PS exposure and depletion of glutathione were observed along with enhanced splenic sequestration of erythrocytes. In conclusion, these results suggest that beta L-induced anemia might be mediated through the PS exposure and subsequent erythrophagocytosis, providing novel insight into the drug-induced anemia.