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ToxSci Advance Access originally published online on August 17, 2005
Toxicological Sciences 2005 88(1):274-283; doi:10.1093/toxsci/kfi290
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Lipids versus Proteins as Major Targets of Pro-Oxidant, Direct-Acting Hemolytic Agents

David C. McMillan*,1, Christine L. Powell*, Zachary S. Bowman*, Jason D. Morrow{dagger} and David J. Jollow*

* Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, South Carolina 29425, and {dagger} Department of Medicine and Pharmacology, Vanderbilt University, Nashville, Tennessee 37232

Received July 5, 2005; accepted August 12, 2005

Lipid peroxidation and the accompanying translocation of phosphatidylserine (PS) from the inner to the outer leaflet of the lipid bilayer have recently been identified as key components of a signaling pathway for phagocytosis of apoptotic cells by macrophages. Drug-induced hemolytic anemia has long been known to be caused by an accelerated uptake of damaged (but intact) erythrocytes by macrophages in the spleen, and this process has been associated with enhanced formation of reactive oxygen species (ROS). However, the role of lipid peroxidation in hemolytic injury has remained unclear, and the effect of hemolytic agents on the distribution of PS in the erythrocyte membrane is unknown. The present studies were undertaken to determine whether lipid peroxidation and PS translocation could be detected in rat and human erythrocytes by three types of direct-acting hemolytic agents—dapsone hydroxylamine, divicine hydroquinone, and phenylhydrazine. 2',7'-Dichlorodihydrofluorescein diacetate was employed as a probe for intracellular ROS formation; lipid peroxidation was assessed by GC/MS analysis of F2-isoprostanes; and PS externalization was measured by annexin V labeling and the prothrombinase assay. The data confirmed that all three hemolytic agents generate ROS within erythrocytes under hemolytic conditions; however, no evidence for lipid peroxidation or PS translocation was detected. Instead, ROS production by these hemolytic agents was associated with extensive binding of oxidized and denatured hemoglobin to the membrane cytoskeleton. The data suggest that the transmembrane signal for macrophage recognition of hemolytic injury may be derived from oxidative alterations to erythrocyte proteins rather than to membrane lipids.

Key Words: erythrocyte; hemoglobin; hemolytic anemia; lipid peroxidation; phosphatidylserine translocation; reactive oxygen species.


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