RT Journal Article
SR Electronic
T1 A Naphthoquinone Derivative Can Induce Anemia through Phosphatidylserine Exposure-Mediated Erythrophagocytosis
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 414
OP 420
DO 10.1124/jpet.109.164608
VO 333
IS 2
A1 Ji-Yoon Noh
A1 Jong-Sook Park
A1 Kyung-Min Lim
A1 Keunyoung Kim
A1 Ok-Nam Bae
A1 Seung-Min Chung
A1 Sue Shin
A1 Jin-Ho Chung
YR 2010
UL http://jpet.aspetjournals.org/content/333/2/414.abstract
AB A naphthoquinone derivative, β-lapachone (βL; 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 βL in rats induced anemia, i.e., a significantly decreased erythrocyte count. In this study, in an effort to elucidate the mechanism underlying the βL-induced anemia, we investigated the effects of βL on erythrocytes with freshly isolated human erythrocytes in vitro and rat in vivo. βL did not induce erythrocyte hemolysis, indicating that direct hemotoxicity was not involved in βL-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 βL. The PS exposure on erythrocytes was from βL-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 βL-treated erythrocyte in vitro showed increased erythrophagocytosis, demonstrating that the removal of erythrocyte by macrophage can be facilitated by βL-induced PS exposure. In good accordance with these in vitro results, after oral administration of βL in rats, increased PS exposure and depletion of glutathione were observed along with enhanced splenic sequestration of erythrocytes. In conclusion, these results suggest that βL-induced anemia might be mediated through the PS exposure and subsequent erythrophagocytosis, providing novel insight into the drug-induced anemia. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics