Linus Pauling Institute

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) formation were remarkably delayed by penicillamine. Further investigation showed that TCSQ 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 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.