The Protective Effect of Sulfite on Menadione‐ and Diquat‐Induced Cytotoxicity in Isolated Rat Hepatocytes

Abstract

Menadione and diquat cause toxicity in isolated hepatocytes. The toxicities of both menadione and diquat are primarily due to redox cycling and consequent oxidative stress. Menadione toxicity, however, has another component as the compound also possesses alkylating and oxidating properties allowing it to interact directly with cellular nucleophiles. Sulfite afforded considerable protection of isolated rat hepatocytes against the toxicity of menadione. This protective effect of sulfite may have several components. Sulfite effectively competed with glutathione (GSH) for conjugation with menadione, sparing intracellular GSH which may continue to detoxify reactive oxygen species formed through menadione redox cycling. The menadione sulfite conjugate undergoes much slower redox cycling than both menadione and the menadione glutathione conjugate. Sulfite also showed some degree of protection of hepatocytes from the toxicity of diquat. Diquat is a "pure" redox cycling agent and the protective effect of sulfite may involve the liberation of GSH from GSSG by sulfitolysis. This would again bolster intracellular GSH levels allowing further GSH-dependent detoxification of reactive oxygen species through cellular GSH peroxidases. In conclusion, our data illustrate the potential of inorganic sulfite to support the intracellular detoxification function of GSH, both against reactive electrophilic metabolites and against agents undergoing redox cycling.