The effect of diethyldithiocarbamate on the biodisposition of MPTP: an explanation for enhanced neurotoxicity.
Diethyldithiocarbamate (DDC) has been reported to exacerbate the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice. In this study, the effects of DDC on the biotransformation and distribution of MPTP and 1-methyl-4-phenylpyridinium ion (MPP+, the putative toxic metabolite of MPTP) were investigated. When DDC was administered prior to a standardized dosage of MPTP, the initial concentrations of MPTP in striatum, ventral mesencephalon and frontal cortex were markedly increased when compared to animals given MPTP alone. The pre-administration of DDC also produced increased concentrations of MPP+ in these regions at all time points studied. Further, the rate of disappearance of MPP+ from brain was significantly less in DDC pretreated animals, when compared to animals given MPTP alone. In vitro studies, using either brain homogenates or partially purified MAO-B, showed that DDC enhanced the biotransformation of MPTP. These results suggest that DDC enhances MPTP-induced neurotoxicity by increasing brain concentrations of MPP+. Factors contributing to this increase appear to include greater delivery of MPTP to the central nervous system (CNS), increased biotransformation of MPTP to MPP+ via MAO, and possibly reduced clearance of MPP+ from the brain.
Irwin
I
I
Institute for Medical Research, San Jose, CA 95128.
Wu
E Y
EY
DeLanney
L E
LE
Trevor
A
A
Langston
J W
JW
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D001711:Biotransformation / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004050:Ditiocarb / Q000633:toxicity*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008995:Monoamine Oxidase / Q000378:metabolism; D011725:Pyridines / Q000493:pharmacokinetics* / Q000633:toxicity; D014018:Tissue Distribution
D011725:Pyridines; D004050:Ditiocarb; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008995:Monoamine Oxidase