MODULATION OF NONPROTEIN SULFHYDRYL COMPOUNDS RHYTHM WITH BUTHIONINE SULFOXIMINE - RELATIONSHIP WITH OXALIPLATIN TOXICITY IN MICE

The relationship between the rhythm in tissue nonprotein sulphydryl gr oups (NPSH) and that in 1,2-diamine (traus-I)-cyclohexane oxalatoplati num (I-OHP) toxicity was investigated in a total of 266 male B(6)D(2)F 1 mice, using buthionine sulphoximine (BSO), an inhibitor of gamma-glu tamylcysteine synthetase. Mice were synchronized with an alternation o f 12 h light (L) and 12 h darkness (D; LD 12:12),and circadian time wa s expressed in hours after tight onset (HALO). NPSH was measured in li ver, jejunum and bone marrow 0, 8 and 16 HALO. Dosing 1-OHP at these t imes achieved intermediate. high or low toxicity respectively. The phy siological circadian rhythm in NPSH content was statistically signific ant in all tissues studied, with a maximum at the transition from D to L (0 HALO). BSO administration (450 mg/kg i.p., lh before sampling) i nduced a large depletion in liver and jejunum NPSH at their physiologi cal peak (0 HALO), but exerted no significant effect at their trough ( 8 HALO). As a result, 24 h rhythm was suppressed in liver and jejunum. but remained similar to the physiological one in bone marrow. BSO enh anced 1-OHP-induced mortality and jejunal toxicity, but exerted no sig nificant effect upon bone marrow toxicity. Despite these differences. I-OHP remained least toxic at 16 HALO. near the middle of the dark spa n, which corresponds to maximum activity in the circadian rest/activit y cycle. Our results show that mean NPSH levels in liver seem to accou nt for the mean level of 1-OHP toxicity, while jejunal NPSH rhythm pla ys an important role in the intestinal toxicity rhythm of this drug.