Pharmacologic modulation of reduced glutathione circadian rhythms with buthionine sulfoximine: relationship with cisplatin toxicity in mice

Abstract

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.