Effect of sulphydryl drugs on paracetamol-induced hepatotoxicity in mice

It has been shown that the major in vivo biotransformation of thiol-containing drugs such as captopril (CP) and penicillamine (PA) involve mixed disulphide formation with endogenous thiols derived from cysteine. At high doses, both drugs produced a dose-dependent depletion of glutathione (GSH) and may perturb GSH and related GSH-enzymes. In this study the possible interactions of these drugs with paracetamol, which produce hepatotoxicity after GSH depletion, were investigated. Following co-administration of CP (50-250 mg/kg) or PA (43-257 mg/kg) with paracetamol (300 mg/kg), the hepatotoxic effect produced by paracetamol was diminished. The protective effect was comparable to that produced by N-acetylcysteine (500 mg/kg) and L-cysteine (500 mg/kg). However, pre-treatment with buthionine sulfoximine (BSO), a specific inhibitor of GSH synthesis, abolished the protective effects of CP, N-acetylcysteine and L-cysteine while the protective effect of PA was unaffected. This suggests that, although both CP and PA may act as alternative sulphydryl nucleophiles to GSH to prevent arylation of essential cellular macromolecules by the reactive metabolite of paracetamol, the underlying mechanisms of these drug interactions may be distinctly different.