Cystathionine pathway-dependent cytotoxicities of diethyl maleate and diamide in rat and human hepatoma-derived cell cultures.
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 (- glutamylcysteine synthetase, reduces the GSH content more efficiently in rat (Fa32) than in human (HEp-G2) hepatoma-derived 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.
Dierickx
Paul J
PJ
Laboratorium Biochemische Toxikologie, Instituut voor Volksgezondheid, Afdeling Toxikologie, Wytsmanstraat 14, 1050 Brussels, Belgium.
De Beer
Jacques O
JO
Scheers
Ellen M
EM
D000480:Alkynes / Q000494:pharmacology; D000818:Animals; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects*; D003540:Cystathionine / Q000378:metabolism*; D003542:Cystathionine gamma-Lyase / Q000037:antagonists & inhibitors; D003958:Diamide / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006710:Homocysteine / Q000494:pharmacology; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D008114:Liver Neoplasms, Experimental; D008298:Maleates / Q000633:toxicity*; D008715:Methionine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D014407:Tumor Cells, Cultured
D000480:Alkynes; D004791:Enzyme Inhibitors; D008298:Maleates; D006710:Homocysteine; D003958:Diamide; D003540:Cystathionine; D019328:Buthionine Sulfoximine; C009055:propargylglycine; C006379:N-acetylmethionine; D008715:Methionine; D003542:Cystathionine gamma-Lyase; C014476:diethyl maleate; D005978:Glutathione; D005998:Glycine