Lind M J, McGown A T, Hadfield J A, Thatcher N, Crowther D, Fox B W
CRC Department of Medical Oncology, Paterson Institute for Cancer Research, Christie Hospital, Manchester, U.K.
Biochem Pharmacol. 1989 Jun 1;38(11):1835-40. doi: 10.1016/0006-2952(89)90419-x.
The effect of ifosfamide and its metabolites on intracellular levels of glutathione in P388 cells in vitro has been studied. It is demonstrated that glutathione depletion occurs only in the presence of 4-hydroperoxyifosfamide and chloroacetaldehyde. In contrast isophosphoramide mustard had no effect on glutathione levels in intact cells. The concentration of 4-hydroperoxyifosfamide required to reduce glutathione levels by 50% was approximately 1 mM and this represents a concentration far in excess of that achievable in patients receiving the drug. However the concentration of chloroacetaldehyde (approximately 100 microM) required to reduce intracellular levels of glutathione to a similar extent is attained in patients receiving ifosfamide. The glutathione levels in lymphocytes isolated from a patient undergoing an eight hour infusion of ifosfamide showed a marked decrease to about 30% of their original value. We conclude that ifosfamide causes glutathione depletion in vivo and the majority of this can be accounted for by the production of chloroacetaldehyde.
已研究了异环磷酰胺及其代谢产物对体外P388细胞内谷胱甘肽水平的影响。结果表明，仅在存在4-氢过氧异环磷酰胺和氯乙醛的情况下才会发生谷胱甘肽耗竭。相比之下，异环磷酰胺氮芥对完整细胞中的谷胱甘肽水平没有影响。使谷胱甘肽水平降低50%所需的4-氢过氧异环磷酰胺浓度约为1 mM，这一浓度远远超过接受该药物治疗的患者所能达到的浓度。然而，接受异环磷酰胺治疗的患者体内可达到将细胞内谷胱甘肽水平降低至类似程度所需的氯乙醛浓度（约100 microM）。从一名接受八小时异环磷酰胺输注的患者分离出的淋巴细胞中的谷胱甘肽水平显著下降至其原始值的约30%。我们得出结论，异环磷酰胺在体内会导致谷胱甘肽耗竭，且其中大部分可归因于氯乙醛的产生。
