Butterworth, Michael; (1992) Novel esters of cysteine as potential chemoprotectants. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Novel esters of cysteine have been synthesized to evaluate their potential as chemoprotectants. The increased lipohilicity of the esters relative to cysteine should facilitate their entry into cells. Following hydrolysis, the esters should provide an intracellular source of cysteine, to be utilized either for the synthesis of glutathione (GSH) or to act as a direct nucleophilic chemoprotectant. Several esters of cysteine have previously been show to protect against the acute pulmonary oedema induced by perfluoroisobutene, an electrophilic pyrolysis product of Teflon. Cysteine isopropylester (CIPE) produced a rapid but transient elevation of the levels of non-protein sulphydryls in several mouse organs, which was particularly marked in the lung. In laboratory animals with induced hepatic cytochrome P450 activity, CIPE protected against paracetamol and bromobenzene- induced toxicity. CIPE ameliorated the toxicity of paracetamol as effectively as N-acetylcysteine. However, CIPE did not prevent naphthalene-induced damage to the lung. Following exposure of mice to diethyl maleate, CIPE did not support the replenishment of hepatic GSH, in contrast to N acetylcysteine. CIPE appeared to offer best protection against electrophilic attack of short duration, coinciding with elevated levels of tissue cysteine. High doses of CIPE alone were toxic when administered to mice induced with benzo(a)pyrene but not to control or mice induced with phenobarbitone. In a rat lung slice model, the esters of cysteine, CIPE and cysteine cyclohexylester, produced considerable rises in intracellular cysteine when compared to other potential cysteine delivery systems, cysteine, N-acetylcysteine or L, 2- oxothiazolidine-4-carboxylic acid. All these cysteine delivery systems were capable of replenishing GSH in slices previously depleted of their GSH by diethyl maleate. Cellular esterases played a key role in the metabolism of cysteine esters by isolated cells. Inhibiting esterase activity, while increasing the extracellular half life of the cysteine esters did not greatly increase the pool of unmetabolised ester detected within cells. A novel role for esterase, mediating the rise in cellular cysteine by the esters, is hypothesised. Paraquat is a herbicide whose pulmonary toxicity is associated with its selective accumulation into the lungs via a polyamine uptake system. The iron chelators, desferrioxamine, CP51 and 2, 3-dihydroxybenzoic acid, partially ameliorated the toxicity of paraquat to rat lung slices. Desferrioxamine was the most effective because it also blocked accumulation of paraquat. Exogenous GSH moderately alleviated the toxicity of paraquat but raising the pulmonary content of GSH with phorone pretreatment did not.

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