E. Reyes et al., THE EFFECT OF IN-UTERO ADMINISTRATION OF BUTHIONINE SULFOXIMINE ON RAT DEVELOPMENT, Pharmacology, biochemistry and behavior, 50(4), 1995, pp. 491-497
Glutathione (GSH) is a tripeptide that is thought to be an essential c
ell component playing an important role as a cellular antioxidant and
scavenger of free radicals. GSH depletion has been shown to render cel
ls more sensitive to various insults. GSH has a protective effect. GSH
levels can be decreased by inhibition of its synthesis with buthionin
e sulfoximine (BSO), which inhibits gamma-glutamylcysteine synthetase.
Several studies have shown that treatment with BSO enhances the toxic
ity of some drugs and radiation. A previous study indicated that the e
ffects of BSO on the developing embryo were short lived and did not pe
rsist to birth. In the above-mentioned study, mothers were treated wit
h BSO only on days 10 and 11 of gestation. The objective of the presen
t study was to determine the effects of BSO administration on GSH depl
etion throughout pregnancy on the developing rat. Timed pregnant Sprag
ue-Dawley rats were placed on a liquid BioServ diet containing BSO sta
rting 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 d
iet until gestation day 21 when they were anesthetized with sodium pen
tobarbital and the pups delivered by Cesarean section. GSH levels were
measured in brain and liver, and various parameters relating to devel
opment were assessed. A dose-response curve showed that a maximum depl
etion (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 m
others. GSH levels in brain and liver of the offspring were decreased
by 60% and 66%, respectively. No significant effect of treatment with
BSO was observed on growth-related parameters, such as body or brain w
eight. A significant decrease in neuron-specific enolase (NSE) activit
y in cerebellum and an increase in liver gamma-glutamyl transpeptidase
activity were observed in pups born to mothers treated with BSO. A de
crease in NSE activity consistent with delayed development was observe
d. Therefore, we conclude that although a decrease in GSH may not prod
uce obvious or observable teratogenic effects, it may produce a delay
in development and may have a permissive role in teratogenic effects p
roduced by other drugs by virtue of GSH depletion.