ENHANCED OXYGEN-TOXICITY FOLLOWING TREATMENT WITH 1,3-BIS(2-CHLOROETHYL)-1-NITROSOUREA
ENHANCED OXYGEN-TOXICITY FOLLOWING TREATMENT WITH 1,3-BIS(2-CHLOROETHYL)-1-NITROSOUREA
复制标题
DOI：
10.1016/0272-0590(84)90097-6
复制
发表时间：
1984-01-01
期刊：
影响因子：
--
通讯作者：
PARAIDATHATHU, T
中科院分区：
文献类型：
--
作者：
KEHRER, JP;PARAIDATHATHU, T
抗癌药物 1,3-双(2-氯乙基)-1-亚硝基脲 (BCNU) 可抑制谷胱甘肽还原酶，这是一种参与氧化防御系统的酶。 BNCU 在雄性和雌性 BALB/c 小鼠中的 30 天 LD50 分别为 52 和 46 mg/kg。 35 mg/kg BNCU 剂量对任何动物均不致死。 .apprx 抑制肺组织中的谷胱甘肽还原酶。单次 35 mg/kg 剂量的 BCNU 后 4 天为 50%。 BCNU 对谷胱甘肽还原酶的长期抑制表明该药物可能通过降低肺的抗氧化能力来增强肺氧毒性。与媒介物处理的对照组相比，将用 35 或 50 mg/kg BCNU 处理的小鼠暴露于持续 85% 的氧气中，LT50 [半数致死毒性剂量] 分别从 13.1 天减少到 6.3 天和 5.3 天。所有用 35 mg/kg BCNU 或媒介物处理并仅在第 0-4 天暴露于 85% 氧气的小鼠均存活至第 30 天。将高氧暴露延长 1 天导致所有 BCNU 处理的小鼠死亡，而媒介物处理的小鼠中有 70% 存活至第 30 天。肺谷胱甘肽过氧化物酶、过氧化氢酶和超氧化物歧化酶活性在术后 6 天不受影响35 mg/kg BCNU、85% 氧气或两者兼而有之。肺谷胱甘肽还原酶活性不受单独 85% 氧气的影响，尽管高氧使 BCNU 诱导的这种酶的抑制延长至第 6 天。BCNU，35 mg/kg，对肺还原型谷胱甘肽 (GSH) 水平几乎没有影响。仅在第 4 天才测量到显着下降。高氧，无论是单独使用还是与 BCNU 一起使用，对肺 GSH 含量没有影响。单独使用 BCNU 治疗或与氧气联合治疗时，肺总羟脯氨酸含量（纤维化指数）没有变化。单次 BCNU 剂量 35 mg/kg 或更多可增加高氧的致死作用。这种作用的机制尚不清楚，因为虽然谷胱甘肽还原酶是唯一受到抑制的抗氧化酶活性，但谷胱甘肽水平保持不变。
The anticancer drug 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) inhibits glutathione reductase, an enzyme involved in oxidant defense systems. The 30-day LD50 for BNCU in male and female BALB/c mice was 52 and 46 mg/kg, respectively. A 35-mg/kg BNCU dose was not lethal to any animal. Glutathione reductase was inhibited in lung tissue by .apprx. 50% for 4 days following a single 35 mg/kg dose of BCNU. The prolonged inhibition of glutathione reductase by BCNU suggested this drug might enhance pulmonary oxygen toxicity by diminishing the lung''s antioxidant capacity. Exposing mice treated with 35 or 50 mg/kg BCNU to continuous 85% oxygen decreased the LT50 [median lethal toxicity dose] from 13.1 to 6.3 and 5.3 days, respectively, compared to vehicle-treated controls. All mice treated with 35 mg/kg BCNU or vehicle and exposed to 85% oxygen only on days 0-4 survived to day 30. Extending the hyperoxic exposure 1 additional day resulted in the death of all BCNU-treated mice, while 70% of the vehicle-treated mice survived to day 30. Pulmonary glutathione peroxidase, catalase and superoxide dismutase activities were unaffected up to 6 days following 35 mg/kg BCNU, 85% oxygen, or both. Pulmonary glutathione reductase activity was unaffected by 85% oxygen alone, although hyperoxia extended the BCNU-induced inhibition of this enzyme to day 6. BCNU, 35 mg/kg, had little effect on lung reduced glutathione (GSH) levels. A significant decrease was only measured on day 4. Hyperoxia, either alone or with BCNU, had no effect on lung GSH content. The total lung content of hydroxyproline, an index of fibrosis, was unchanged by BCNU-treatments either alone or in combination with oxygen. Single BCNU doses of 35 mg/kg or more can increase the lethal effect of hyperoxia. The mechanism of this effect remains unclear since, while glutathione reductase was the only antioxidant enzymatic activity inhibited, GSH levels remained unchanged.