The effect of in utero administration of buthionine sulfoximine on rat development.
Glutathione (GSH) is a tripeptide that is thought to be an essential cell component playing an important role as a cellular antioxidant and scavenger of free radicals. GSH depletion has been shown to render cells more sensitive to various insults. GSH has a protective effect. GSH levels can be decreased by inhibition of its synthesis with buthionine sulfoximine (BSO), which inhibits gamma-glutamylcysteine synthetase. Several studies have shown that treatment with BSO enhances the toxicity of some drugs and radiation. A previous study indicated that the effects of BSO on the developing embryo were short lived and did not persist to birth. In the above-mentioned study, mothers were treated with BSO only on days 10 and 11 of gestation. The objective of the present study was to determine the effects of BSO administration on GSH depletion throughout pregnancy on the developing rat. Timed pregnant Sprague-Dawley rats were placed on a liquid BioServ diet containing BSO starting on day 1 of pregnancy. The mothers received a daily dose of BSO ranging from 2 to 6 mmol/kg/24 h. The mothers were maintained on the diet until gestation day 21 when they were anesthetized with sodium pentobarbital and the pups delivered by Cesarean section. GSH levels were measured in brain and liver, and various parameters relating to development were assessed. A dose-response curve showed that a maximum depletion (86%) of GSH in the mother's liver was produced by the 6 mmol/kg dose of BSO. However, no change was seen in brain GSH levels of the mothers.(ABSTRACT TRUNCATED AT 250 WORDS)
Reyes
E
E
Department of Pharmacology, University of New Mexico School of Medicine, Albuquerque 87131, USA.
Ott
S
S
Robinson
B
B
Contreras
R
R
D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000818:Animals; D019328:Buthionine Sulfoximine; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D005260:Female; D005721:Glutamate-Cysteine Ligase / Q000037:antagonists & inhibitors*; D005978:Glutathione / Q000378:metabolism*; D008431:Maternal-Fetal Exchange; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives* / Q000633:toxicity; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione