Reaction of Vanadium (V) with Thiols Generates Vanadium (IV) and Thiyl Radicals

"The in vivo toxicity of vanadium(V) has been found to correlate with the depletion of cellular glutathione and related non-protein thiols. With a view to understanding the mechanism for this observation, we have investigated the oxidation of glutathione, cysteine N·acetylcystcinc and pcnicil· lamine by vanadium(V), using electron spin resonance (ESR) and ESR spin trapping methodology. The spin trap used was 5,5-dimethyl-l-pyrroline I-oxide (DMPO). It is found that the oxidation of these thiols by vanadium(V) generates the corresponding thiyl radicals and vanadilim- (IV) complexes. The results suggest that free radical reactions play a significant role in the depletion of cellular thiols by vanadium(V) and hence in vanadium(V) toxicity. 1. INTRODUCTIONThis communication reports on the identification of thiyl radicals formed as intermediates in the reaction of vanadium(V) with glutathione (GSH) and related nonprotein thiols. This study was undertaken because the biochemical mechanism of vanadium toxicity is still not fully understood,. despite being a topic of current research activity [1-20). As to possible clues, it is known that vanadium is most toxic when administered in its pentavaient state [21), and that vanadium(V) administration into laboratory mice reduces cellular levels of NAD(P)H and GSH [22). While the oxidation of NAD(P)H by vanadium has been studied extensively [16-20), that of glutathione and related non-protein thiols has been paid less attention. On the other hand, GSH and related thiols are important cellular antioxidants [23). Their functions include decomposing lipid peroxides and protecting cell membranes [23-25). Thus any reduction in the cellular contents of such nonprotein thiols after vanadium exposure may result in the accumulation of lipid peroxides which might ultimately lead to tissue injury. With a view of finding the mechanism for this thiol depletion process, we have investigated reactions of non-protein thiols with vanadium(V). Particular attention has been paid to the detection of thiyl radicals, since it has been postulated [l] (but not experimentally proven) that the glutathionyl radical (GS·) might be an intermediate in the reaction between vanadium(V), NADH and GSH. We have used electron spin resonance (ESR) and ESR spin trapping methodology for investigating the reactions of GSH, cysteine, N-acetylcysteine and penicillamine with vanadium(V). The results show that the corresponding thiyl radicals are indeed formed in the one-electron reduction of vanadium(V) by all of the above mentioned thiols."