Skamarauskas, John Timothy; (1991) The Chemistry and Biochemistry of Glutathione and its Role in Mechanisms of Pulmonary Toxicity. Masters thesis (M.Phil), UCL (University College London).

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Abstract

Glutathione, the major cellular nonprotein thiol plays a critical role in cellular defences against oxidative stress and in the detoxification of many electrophiles. A major aim of the studies in this thesis was to assess the relative importance of the protective mechanisms of glutathione in pulmonary toxicity. The roles of glutathione conjugation and redox cycling were assessed in different cell types in the lung. The toxicity of diquat, 2, 3-dimethoxy-l,4 naphthoquinone (2,3-diMeO-NQ), paraquat (redox cycling compounds) and 1,4 benzoquinone (an arylating compound) was investigated using an in vitro lung slice model with inhibited glutathione reductase activity. Toxicity was assessed using biochemical and functional markers. Studies using inhibitors of glutathione peroxidase and catalase suggest possible differences in protection against oxidative stress between cell types. These studies suggest the possibility that the role of glutathione conjugation and redox cycling may possibly differ between cell types in the lung. Adenosine accumulation by rat lung slices was investigated as a potential marker for pulmonary endothelial cell function. Adenosine accumulation was shown to be saturable but does not appear to follow simple Michaelis Menten kinetics. After uptake, adenosine is predominantly phosphorylated to form ATP, but a minor fraction is deaminated to form inosine. The use of metabolic inhibitors suggested that the majority of the metabolism might occur in the cytosol. Microautoradiography showed some localisation of the accumulated adenosine in the region of the pulmonary endothelium. The accumulation of adenosine by rat lung slices may prove to be a useful marker of endothelial cell function in vitro. The influence of raised pulmonary glutathione levels on the in vivo pulmonary toxicity of ?-naphthylthiourea (ANTU) was investigated. It was shown that ANTU is toxic to both the pulmonary endothelium and epithelium. Raised glutathione levels appear to protect against the endothelial, but not the epithelial, toxicity of ANTU.

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