Sood C, O'Brien P J
Faculty of Pharmacy, University of Toronto, Ontario, Canada.
Br J Cancer Suppl. 1996 Jul;27:S287-93.
2-Chloroacetaldehyde (CAA) formed during the metabolism of the anti-cancer drug ifosfamide (IP) has been implicated in ifosfamide-related neurotoxicity during chemotherapy but the neurotoxic mechanisms are unknown. We have found that IP (900 mg kg-1, p.o.) caused lethargy and mild hind limb paralysis after 6 h. Neurotoxicity and IP-induced mortality was markedly enhanced in mice pretreated with either phenobarbital or dexamethasone to induce cytochrome P4503A. Cerebral glutathione (GSH) levels were also markedly depleted in these pretreated mice. 2-Chloroethanol (92 mg kg-1, i.p.) (CE) also caused a 50% reduction in cerebral GSH 6 h after administration to mice. At this time maximum lethargy and unresponsiveness to touch was apparent in CE-treated mice. Severe hind limb paralysis developed and death ensued 12-18 h later. Prior depletion of cerebral GSH with 2-cyclohexene-1-one greatly accelerated the onset of CE-induced neurotoxicity suggesting that cerebral GSH status is an important determinant of CE-induced neurotoxicity. Furthermore, pretreatment with N-acetylcysteine delayed both CE-induced neurotoxicity and cerebral GSH depletion. Induction of cerebral but not hepatic CYP2E1 by ethanol before CE challenge also potentiated CE-induced cerebral GSH depletion and neurotoxicity. Hepatic GSH depletion was unaffected suggesting that CE-induced paralysis is dependent on a cerebral but not a hepatic CYP2E1 catalysed oxidation of CE to CAA. Ethanol was neuroprotective even if given 60 min after CE and prevented further cerebral GSH depletion. 4-Methylpyrazole, a CYP2E1 and alcohol dehydrogenase inhibitor, prevented both CE-induced hepatic and cerebral GSH depletion and paralysis. This suggests that the neurotoxicity associated with IP chemotherapy involves activation of chloroethanol by cerebral CYP2E1 to chloroacetaldehyde which mediates cerebral GSH depletion. Neurotoxicity may be prevented by restoring cerebral GSH status and/or by preventing activation of CE by CYP2E1 with ethanol.
抗癌药物异环磷酰胺（IP）代谢过程中形成的2-氯乙醛（CAA）被认为与化疗期间异环磷酰胺相关的神经毒性有关，但神经毒性机制尚不清楚。我们发现，口服IP（900毫克/千克）6小时后会导致嗜睡和轻度后肢麻痹。用苯巴比妥或地塞米松预处理以诱导细胞色素P4503A的小鼠，神经毒性和IP诱导的死亡率显著增加。这些预处理小鼠的脑内谷胱甘肽（GSH）水平也明显降低。腹腔注射2-氯乙醇（92毫克/千克）（CE）给小鼠后6小时，脑内GSH也减少了50%。此时，CE处理的小鼠出现最大程度的嗜睡且对触摸无反应。12 - 18小时后出现严重的后肢麻痹并导致死亡。用2-环己烯-1-酮预先耗尽脑内GSH大大加速了CE诱导的神经毒性的发作，这表明脑内GSH状态是CE诱导的神经毒性的重要决定因素。此外，用N-乙酰半胱氨酸预处理可延迟CE诱导的神经毒性和脑内GSH消耗。在CE攻击前用乙醇诱导脑内而非肝内的CYP2E1也增强了CE诱导的脑内GSH消耗和神经毒性。肝内GSH消耗未受影响，这表明CE诱导的麻痹依赖于脑内而非肝内的CYP2E催化CE氧化为CAA。即使在CE给药60分钟后给予乙醇也具有神经保护作用，并可防止脑内GSH进一步消耗。4-甲基吡唑，一种CYP2E1和乙醇脱氢酶抑制剂，可防止CE诱导的肝内和脑内GSH消耗以及麻痹。这表明与IP化疗相关的神经毒性涉及脑内CYP2E1将氯乙醇激活为氯乙醛，后者介导脑内GSH消耗。通过恢复脑内GSH状态和/或通过用乙醇防止CYP2E1激活CE，可能预防神经毒性。
