Redox cycling of MPP+: evidence for a new mechanism involving hydride transfer with xanthine oxidase, aldehyde dehydrogenase, and lipoamide dehydrogenase.
MPP+ is redox active in the presence of cytochrome P450 reductase and induces the formation of O2.- and HO(.). In this study, we report the redox cycling capability of MPP+ with additional enzymes and with UV photolysis detected through ESR techniques. The treatment of MPP+ with UV light resulted in the production of HO. trapped as a spin adduct. Two of the enzymes examined in this study, xanthine oxidase and aldehyde dehydrogenase, produced O2.- in the presence of substrate. However, when MPP+ was added to the incubations, the radical trapped by DMPO was HO(.). This indicates that MPP+ redox cycles in the presence of these two enzymes or UV light, which produces HO.. Our data also suggest that MPP+ is reduced by lipoamide dehydrogenase. MPP+ stimulated the oxidation of reduced nicotinamide adenine dinucleotide (NADH) by the enzyme at concentrations between 2 mM and 8 mM of MPP+. Higher concentrations of MPP+ inhibited lipoamide dehydrogenase. MPP+ appears to be redox active with a number of redox enzymes. The mechanism involved may be hydride transfer from the enzymes to MPP+, rather than a direct single-electron reduction.
Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Los Angeles 90033.
L K
LK
Klaidman
J D
JD
Adams
A C
AC
Leung
S S
SS
Kim
E
E
Cadenas
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000378:metabolism*; D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism* / Q000494:pharmacology; D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D008058:Dihydrolipoamide Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D006878:Hydroxides / Q000378:metabolism; D017665:Hydroxyl Radical; D009243:NAD / Q000378:metabolism; D010084:Oxidation-Reduction; D010782:Photolysis; D013481:Superoxides / Q000378:metabolism; D014466:Ultraviolet Rays; D014969:Xanthine Oxidase / Q000378:metabolism*
D006878:Hydroxides; D009243:NAD; D013481:Superoxides; D017665:Hydroxyl Radical; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014969:Xanthine Oxidase; D000444:Aldehyde Dehydrogenase; D008058:Dihydrolipoamide Dehydrogenase; D015655:1-Methyl-4-phenylpyridinium