259 - Molecular Mechanism of an Unexpected Novel Antioxidant-Like Activity for the Classic Copper-Chelating Drug Penicillamine

Abstract

Penicillamine has been widely used clinically as a copper-chelating drug for the treatment of copper overload in Wilson’s disease. Here we found that penicillamine, but not the classic copper chelating agent bathocuproine disulfonate (BCS), provided marked protection against cell cytotoxicity induced by tetrachlorohydroquinone (TCHQ), a major toxic metabolite of the widely used wood preservative pentachlorophenol. The autooxidation process of TCHQ yielding the reactive tetrachlorosemiquinone (TCSQ●–) radical was studied by ESR and UV-visible spectral methods. We found, unexpectedly, the autooxidation process of TCHQ and the time course of TCSQ●– radical formation was remarkably delayed by penicillamine in a concentration dependent manner; In contrast, no delaying effect was observed by BCS. HPLC-MS and ESR studies showed that TCSQ●– radical was reduced to TCHQ by penicillamine, which was concurrently oxidized to its corresponding disulfide form. These data suggest that the protection by penicillamine on TCHQ-induced cytotoxicity was not due to its binding of copper, but rather to its reduction of the reactive TCSQ●– radical to the much less reactive TCHQ. This is the first report demonstrating an unexpected novel antioxidant-like activity for this copper-chelating amino thiol drug, which might prove highly relevant to the biological and pharmaceutical activities of penicillamine.