Dopamine (DA) quinone as DA neuron-specific oxidative stress conjugates with cysteine residues in functional proteins to form quinoproteins. Here, we examined the effects of cysteine-rich metal-binding proteins, metallothionein (NIT)-1 and -2, on DA quinone-induced neurotoxicity. NIT quenched DA semiquinones in vitro. In dopaminergic cells, DA exposure increased quinoproteins and decreased cell viability; these were ameliorated by pretreatment with MT-inducer zinc. Repeated L-DOPA administration markedly elevated striatal quinoprotein levels and reduced the DA nerve terminals specifically on the lesioned side in NIT-knockout parkinsonian mice, but not in wild-type mice. Our results suggested that intrinsic NIT protects against L-DOPA-induced DA quinone neurotoxicity in parkinsonian mice by its quinone-quenching property. (c) 2007 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.