PHARMACOLOGICAL MODULATION OF REDUCED GLUTATHIONE CIRCADIAN-RHYTHMS WITH BUTHIONINE SULFOXIMINE - RELATIONSHIP WITH CISPLATIN TOXICITY IN MICE

The relationship between the rhythm in reduced glutathione (GSH) and t hat in cisplatin (CDDP) toxicity was investigated in a total of 560 ma le B6D2F1 mice, using buthionine sulfoximine (BSO). GSH was measured b y high-performance liquid chromatography (HPLC) in four tissues, at ea ch of six sampling times, 4 hr apart. A significant 24-hr rhythm was s tatistically validated in liver, jejunum, and colon, but not in bone m arrow. 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 variat ion. This rhythm may reflect that in the activity of GSH-degrading enz ymes. BSO (450 mg/kg ip, 4 hr before sampling) reduced liver GSH three fold and kidney cysteine content was halved, but this pretreatment had no significant effect upon GSH content in the other organs. Furthermo re, 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 resu lt from an unmasking of the 12-hr rhythm in GSH-degrading enzyme activ ity by GSH synthesis blockade. Maximal values occurred in the mid-rest span and in the mid-active span after BSO administration. In the othe r tissues, the 24-hr period remained unchanged. BSO injection largely enhanced CDDP toxicity (as assessed by survival, leukopenia, and histo logic lesions in kidney and bone marrow) and kidney mean platinum conc entration. Furthermore, BSO pretreatment modified the period of CDDP t oxicity rhythm: survival followed a significant 12-hr-rhythm, instead of a 24-hr rhythm. The cycling of GSH concentration results from a bal ance between synthesis and catabolism and likely constitutes one of th e main components of the circadian rhythm in CDDP toxicity in mice. (C ) 1997 Academic Press.