Role of oxidative stress and glutathione in busulfan toxicity in cultured murine hepatocytes.
This study examines busulfan metabolism. Busulfan given in vivo or in vitro decreased hepatocyte glutathione (GSH) by 60 and 50%, respectively. In vitro, busulfan toxicity was prevented by glutathione S-transferase inhibitors or by antioxidants and led to increased production of oxidized GSH and thiobarbituric acid reactive substances. 'Rescue' from toxicity by GSH precursors was prevented by N,N-bis(2-chloroethyl)-N-nitrosourea (BCNU). Depletion of GSH exacerbated toxicity. In GSH-depleted hepatocytes, busulfan decreased GSH by 95% and BCNU did not prevent rescue by GSH precursors.


CONCLUSIONS
(1) In hepatocytes with normal GSH: busulfan toxicity requires GSH conjugation, does not cause profound GSH depletion and is mediated by oxidative stress. We postulate that a GSH conjugate promotes oxidative stress. (2) In GSH-depleted hepatocytes: busulfan profoundly depletes GSH; toxicity is mediated by oxidative stress and is prevented by restoring GSH levels; cell death may be due to unopposed endogenous oxidative stress.
DeLeve
L D
LD
Division of Gastrointestinal and Liver Diseases and Center for Liver Disease Research, Department of Medicine, USC School of Medicine, Los Angeles, CA, USA. deleve@hsc.usc.edu
Wang
X
X
D000477:Alkylating Agents / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002066:Busulfan / Q000378:metabolism / Q000494:pharmacology*; D002478:Cells, Cultured; D005978:Glutathione / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D000477:Alkylating Agents; D017392:Thiobarbituric Acid Reactive Substances; D002066:Busulfan; D005978:Glutathione