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Alternatives to Laboratory Animals - ATLA

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Cystathionine Pathway-dependent Cytotoxicities of Diethyl Maleate and Diamide in Rat and Human Hepatoma-derived Cell Cultures

Paul J. Dierickx, Jacques O. De Beer and Ellen M. Scheers

Glutathione (GSH) plays a role in many toxicologically important metabolic processes. It was previously established that L-buthionine S,R-sulphoximine (BSO), a specific inhibitor of γ-glutamylcysteine synthetase, reduces the GSH content more efficiently in rat (Fa32) than in human (Hep G2) hepatomaderived cells. We therefore investigated whether the cystathionase inhibitor propargylglycine (PPG) could further decrease the BSO-induced GSH depletion in Hep G2 cells. The influence of the cystathionine precursors N-acetylmethionine, methionine and homocysteine on the cytotoxicity of diethyl maleate (DEM) and diamide [1,1´-azobis(N,N-dimethylformamide)] was also investigated. PPG reduced the GSH content in both cell lines. A further GSH decrease in Hep G2 was obtained when using a BSO + PPG combination containing relatively high concentrations of PPG. BSO diminished the toxicity of PPG. Homocysteine was the most efficacious of the tested cystathionine precursors in increasing the GSH content and reducing the cytotoxicity of DEM and diamide in Fa32 and Hep G2 cells.