An unexpected antioxidant and redox activity for the classic copper-chelating drug penicillamine

Penicillamine has been widely-used clinically as a copper-chelating drug for the treatment of copper-overload in Wilson's disease. In this study, we found that penicillamine provided marked protection against cytotoxicity induced by tetrachlorohydroquinone (TCHQ), a major toxic metabolite of the well-known wood preservative pentachlorophenol, while other classic copper-chelating agents do not. We found, unexpectedly, that both TCHQ autooxidation and tetrachlorosemiquinone radical (TCSQ(center dot-)) formation were remarkably delayed by penicillamine. Further investigation showed that TCSQ(center dot-) was reduced back to TCHQ by penicillamine, with the concurrent formation of its corresponding disulfide. These data demonstrated that the protection by penicillamine against TCHQ-induced toxicity was not due to its classic Cu-chelating property, but rather to its reduction of the reactive TCSQ(center dot-) to the much less-reactive TCHQ. This is the first report of an unexpected antioxidant and redox activity for penicillamine, which might prove highly relevant to its biological activities.