Partial prevention of glutathione depletion in rats following acute intoxication with diethylmaleate.
To assess the ability of L-2-oxothiazolidine-4-carboxylate (OTC) to stimulate the biosynthesis of glutathione (GSH) in non-fasted male rats, the time-courses of GSH and cysteine contents were studied in liver, kidney, heart and brain, following a single intraperitoneal injection of OTC (5 mmol/kg), with or without co-administration of the GSH depletor diethylmaleate (3 mmol/kg). In the absence of diethylmaleate, OTC did not change the GSH or cysteine content of heart and kidney. The liver was the only organ where systemic administration of OTC resulted in a fast and quasi-linear increase in GSH as a function of time, with no appreciable lag-time. A maximal, i.e. 2.1-fold increase in liver GSH was induced by OTC at the times corresponding to the low GSH values of the diurnal cycle observed in control rats. A smaller, i.e. 1.4-fold increase in brain GSH was observed after 6 hours. A marked increase in cysteine always preceded that of GSH in liver and brain. In the liver, the OTC-mediated stimulation of GSH biosynthesis was optimal when cysteine delivery was achieved at the onset of the cysteine decrease that was observed in the diurnal cycle of control rats. These results support the view that cysteine is a limiting factor in the biosynthesis of GSH. Following an acute dose of diethylmaleate (3 mmol/kg), OTC afforded a general and significant protection of rat tissues against GSH depletion.(ABSTRACT TRUNCATED AT 250 WORDS)
Gerard-Monnier
D
D
Centre de Recherche Roussel-UCLAF, Romainville, France.
Fougeat
S
S
Gourvest
J F
JF
Chaudiére
J
J
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003545:Cysteine / Q000378:metabolism; D005978:Glutathione / Q000096:biosynthesis / Q000172:deficiency*; D006321:Heart / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008298:Maleates / Q000633:toxicity*; D009206:Myocardium / Q000378:metabolism; D011761:Pyrrolidonecarboxylic Acid; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000494:pharmacology*; D053778:Thiazolidines
D008298:Maleates; D013844:Thiazoles; D053778:Thiazolidines; C014476:diethyl maleate; D005978:Glutathione; D003545:Cysteine; D011761:Pyrrolidonecarboxylic Acid; C029536:2-oxothiazolidine-4-carboxylic acid