Modulation of nonprotein sulphydryl compounds rhythm with buthionine sulphoximine: relationship with oxaliplatin toxicity in mice.
The relationship between the rhythm in tissue nonprotein sulphydryl groups (NPSH) and that in 1,2-diamine (trans-I)-cyclohexane oxalatoplatinum (1-OHP) toxicity was investigated in a total of 266 male B6D2F1 mice, using buthionine sulphoximine (BSO), an inhibitor of gamma-glutamylcysteine synthetase. Mice were synchronized with an alternation of 12 h light (L) and 12 h darkness (D; LD 12:12), and circadian time was expressed in hours after light onset (HALO). NPSH was measured in liver, jejunum and bone marrow at 0, 8 and 16 HALO. Dosing 1-OHP at these times achieved intermediate. high or low toxicity respectively. The physiological circadian rhythm in NPSH content was statistically significant in all tissues studied, with a maximum at the transition from D to L (0 HALO). BSO administration (450 mg/kg i.p., 4 h before sampling) induced a large depletion in liver and jejunum NPSH at their physiological 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 enhanced 1-OHP-induced mortality and jejunal toxicity, but exerted no significant effect upon bone marrow toxicity. Despite these differences, 1-OHP remained least toxic at 16 HALO, near the middle of the dark span, which corresponds to maximum activity in the circadian rest/activity cycle. Our results show that mean NPSH levels in liver seem to account for the mean level of 1-OHP toxicity, while jejunal NPSH rhythm plays an important role in the intestinal toxicity rhythm of this drug.
Li
X M
XM
Laboratoire Rythmes Biologiques & Chronothérapeutique, ICIG, Hôpital Paul-Brousse, Villejuif, France.
Metzger
G
G
Filipski
E
E
Lemaigre
G
G
Lévi
F
F
D000704:Analysis of Variance; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects; D019328:Buthionine Sulfoximine / Q000494:pharmacology*; D002940:Circadian Rhythm; D005269:Femur / Q000187:drug effects; D007421:Intestine, Small / Q000187:drug effects*; D007583:Jejunum / Q000187:drug effects; D008099:Liver / Q000737:chemistry / Q000187:drug effects*; D008297:Male; D051379:Mice; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D000077150:Oxaliplatin; D011506:Proteins / Q000378:metabolism; D011897:Random Allocation; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D013997:Time Factors
D009944:Organoplatinum Compounds; D011506:Proteins; D013438:Sulfhydryl Compounds; D000077150:Oxaliplatin; D019328:Buthionine Sulfoximine