Glutathione status in chemical embryotoxicity: Synthesis, turnover and adduct formation

Glutathione (GSH) status has been shown to play a major role in the protection of developing rodent embryos from chemical insult during the teratogen-sensitive period of early organogenesis. Intracellular GSH concentrations in the embryo proper and visceral yolk sac are significant and appear to be regulated spatially and temporally during normal development and in response to chemical exposure. Selective modulation of GSH status in the conceptus in vitro has provided important information regarding the synthesis, utilization and turnover of GSH, as well as its role in protecting the developing embryo from electrophiles, free radicals and oxidative damage. Studies with the embryotoxic metabolite of 2-acetylaminofluorene, 2-nitrosofluorene (NOF), have shown that, although NOF forms adducts with GSH and that proper GSH status is critical for embryo protection, the most likely mechanism of protection is not through adduct formation. The GSH-dependent metabolism of NOF to aminofluorene, a less toxic product, appears to be responsible for the reduction of embryotoxicity when GSH synthesis is stimulated with a cysteine pro-drug. Additional studies have shown that the glutathione disulfide (GSSG) formed in the course of bioactivation, peroxidative metabolism and as a result of oxidative stress may be a common mediator in a number of embryotoxicities. Evaluation of the direct oxidation of GSH through exposure to the thiol oxidant diamide has shown that the teratogenicity or embryotoxicity of diverse chemicals could be mediated through the direct alteration of GSH status, leading to disruption of normal cellular homoeostasis and to alterations in important biochemical pathways as a result of the S-thiolation of critical protein sulfhydryls.