The putative benzene metabolite 2,3, 5-tris(glutathion-S-yl)hydroquinone depletes glutathione, stimulates sphingomyelin turnover, and induces apoptosis in HL-60 cells.
In this study, we show that 2,3,5-tris(glutathion-S-yl)hydroquinone (TGHQ), a putative metabolite of benzene, induces apoptosis in human promyelocytic leukemia (HL-60) cells. Prior to the onset of apoptosis, TGHQ depletes intracellular glutathione (GSH) in a reactive oxygen species (ROS)-independent manner. Neutral, Mg(2+)-dependent sphingomyelinases, which are normally inhibited by GSH, are subsequently activated, as evidenced by increases in intracellular ceramide and depletion of sphingomyelin. As ceramide levels rise, effector caspase (DEVDase) activity steadily increases. Interestingly, while catalase has no effect on TGHQ-mediated depletion of GSH, this hydrogen peroxide (H(2)O(2)) scavenger does inhibit DEVDase activity and apoptosis, provided the enzyme is added to HL-60 cells before an increase in ceramide can be observed. Since ceramide analogues inhibit the mitochondrial respiratory chain, these data imply that ceramide-mediated generation of H(2)O(2) is necessary for the activation of effector caspases-3 and/or -7, and apoptosis. In summary, these studies indicate that TGHQ, and perhaps many quinol-based toxicants and chemotherapeutics, may induce apoptosis in hematopoietic cells by depleting GSH and inducing the proapoptotic ceramide-signaling pathway.
Bratton
S B
SB
Center for Molecular and Cellular Toxicology, Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas at Austin, 78712, USA.
Lau
S S
SS
Monks
T J
TJ
D017209:Apoptosis / Q000187:drug effects*; D001554:Benzene / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000031:analogs & derivatives* / Q000187:drug effects* / Q000378:metabolism / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology*; D010718:Phosphatidylserines / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000502:physiology; D013109:Sphingomyelins / Q000378:metabolism*
D006873:Hydroquinones; D010718:Phosphatidylserines; D017382:Reactive Oxygen Species; D013109:Sphingomyelins; C078765:2,3,5-(triglutathion-S-yl)hydroquinone; D020169:Caspases; D005978:Glutathione; D001554:Benzene