Li X M, Metzger G, Filipski E, Boughattas N, Lemaigre G, Hecquet B, Filipski J, Levi F
Laboratoire Rythmes Biologiques & Chronotherapeutique, ICIG, Hopital Paul-Brousse, Villejuif, France.
Toxicol Appl Pharmacol. 1997 Apr;143(2):281-90. doi: 10.1006/taap.1996.8088.
The relationship between the rhythm in reduced glutathione (GSH) and that in cisplatin (CDDP) toxicity was investigated in a total of 560 male B6D2F1 mice, using buthionine sulfoximine (BSO). GSH was measured by high-performance liquid chromatography (HPLC) in four tissues, at each of six sampling times, 4 hr apart. A significant 24-hr rhythm was statistically validated in liver, jejunum, and colon, but not in bone marrow. Relative to liver, glutathione content was 56% in colon, 38% in bone marrow, 25% in jejunum, and negligible in kidney, where cysteine, a final product of GSH catabolism, displayed a 12-hr rhythmic variation. This rhythm may reflect that in the activity of GSH-degrading enzymes. BSO (450 mg/kg ip, 4 hr before sampling) reduced liver GSH threefold and kidney cysteine content was halved, but this pretreatment had no significant effect upon GSH content in the other organs. Furthermore, the period of the physiologic liver GSH rhythm changed from 24 hr to a composite (24 + 12 hr) period. This change in the period may result from an unmasking of the 12-hr rhythm in GSH-degrading enzyme activity by GSH synthesis blockade. Maximal values occurred in the mid-rest span and in the mid-active span after BSO administration. In the other tissues, the 24-hr period remained unchanged. BSO injection largely enhanced CDDP toxicity (as assessed by survival, leukopenia, and histologic lesions in kidney and bone marrow) and kidney mean platinum concentration. Furthermore, BSO pretreatment modified the period of CDDP toxicity rhythm: survival followed a significant 12-hr-rhythm, instead of a 24-hr rhythm. The cycling of GSH concentration results from a balance between synthesis and catabolism and likely constitutes one of the main components of the circadian rhythm in CDDP toxicity in mice.
使用丁硫氨酸亚砜胺（BSO），在总共560只雄性B6D2F1小鼠中研究了还原型谷胱甘肽（GSH）的节律与顺铂（CDDP）毒性节律之间的关系。每隔4小时在六个采样时间点，通过高效液相色谱法（HPLC）测量四个组织中的GSH。肝脏、空肠和结肠中具有显著的24小时节律，经统计学验证，但骨髓中没有。相对于肝脏，结肠中的谷胱甘肽含量为56%，骨髓中为38%，空肠中为25%，肾脏中可忽略不计，而GSH分解代谢的终产物半胱氨酸在肾脏中呈现12小时的节律变化。这种节律可能反映了GSH降解酶活性的节律。BSO（腹腔注射450mg/kg，采样前4小时）使肝脏GSH降低了三倍，肾脏半胱氨酸含量减半，但这种预处理对其他器官中的GSH含量没有显著影响。此外，生理性肝脏GSH节律的周期从24小时变为复合（24 + 12小时）周期。周期的这种变化可能是由于GSH合成受阻而使GSH降解酶活性的12小时节律显现出来。在BSO给药后的休息中期和活动中期出现最大值。在其他组织中，24小时周期保持不变。BSO注射大大增强了CDDP毒性（通过生存、白细胞减少以及肾脏和骨髓中的组织学损伤评估）和肾脏平均铂浓度。此外，BSO预处理改变了CDDP毒性节律的周期：生存遵循显著的12小时节律，而不是24小时节律。GSH浓度的循环是合成与分解代谢之间平衡的结果，可能构成小鼠CDDP毒性昼夜节律的主要组成部分之一。
