title: Role of oxidative stress and glutathione in busulfan toxicity in cultured murine hepatocytes.
abstract: 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.
authors.affiliation: 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
authors.forename: L D
authors.initials: LD
authors.lastname: DeLeve
authors.forename: X
authors.initials: X
authors.lastname: Wang
mesh_terms: 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
chemical_list: D000477:Alkylating Agents; D017392:Thiobarbituric Acid Reactive Substances; D002066:Busulfan; D005978:Glutathione