title: Ifosfamide induced depletion of glutathione in human peripheral blood lymphocytes and protection by mesna.
abstract: We studied the effects of ifosfamide and major metabolites on intracellular glutathione (GSH) levels in human peripheral blood lymphocytes (PBL). In vitro exposure of PBL to 4-hydroperoxyifosfamide (4-OOH-IF), acrolein or chloroacetaldehyde at 37 degrees C for 60 min led to a concentration dependent depletion of intracellular GSH. The concentration of the three metabolites to cause a 50% depletion of GSH in PBL was in the micromolar range (acrolein: 16 +/- 4 microM; 4-OOH-IF: 22 +/- 9 microM; chloroacetaldehyde: 30 +/- 7 microM). Exposure to ifosfamide, the non-activated drug, had no effects on the intracellular GSH levels. Pretreatment with 4-OOH-IF suppressed dose-dependently the interleukin-2-induced proliferation of PBL. Incubation of PBL together with 2-mercaptoethanesulfonate (mesna) and 4-OOH-IF, acrolein or chloroacetaldehyde prevented the GSH depletion. The protecting effect of mesna in combination with 4-OOH-IF was independent of GSH biosynthesis, because addition of buthionine sulfoximine had no significant influence on this effect. These findings indicate a novel protective mechanism of mesna against intracellular GSH depletion of PBL during exposure to metabolites of ifosfamide.
authors.affiliation: GSF-Institut für Klinische Hämatologie, München, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Meier
authors.forename: A
authors.initials: A
authors.lastname: Allenbacher
authors.forename: E
authors.initials: E
authors.lastname: Mueller
authors.forename: G
authors.initials: G
authors.lastname: Multhoff
authors.forename: C
authors.initials: C
authors.lastname: Botzler
authors.forename: M
authors.initials: M
authors.lastname: Wiesnet
authors.forename: R
authors.initials: R
authors.lastname: Issels
mesh_terms: D000079:Acetaldehyde / Q000031:analogs & derivatives / Q000494:pharmacology; D000171:Acrolein / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D005978:Glutathione / Q000097:blood* / Q000378:metabolism; D006801:Humans; D007069:Ifosfamide / Q000031:analogs & derivatives / Q000494:pharmacology*; D007424:Intracellular Fluid / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism*; D015080:Mesna / Q000494:pharmacology*
chemical_list: C012353:hydroperoxyisophosphamide; D000171:Acrolein; C004656:chloroacetaldehyde; D005978:Glutathione; D000079:Acetaldehyde; D015080:Mesna; D007069:Ifosfamide