Studies on the interactions of MPTP(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) with the cytochrome P-450 enzyme system--clues to a possible aetiological factor in Parkinson's disease.
Idiopathic Parkinson's disease has been postulated to result from exposure to environmental toxins similar to the parkinsonism-causing neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). This study examines the interactions of MPTP with the cytochrome P-450 system--an enzyme system which is known to be involved in the detoxication of MPTP. In vitro studies, using control hepatic microsomes, studied changes in cytochrome P-450 content and enzyme activity with varying concentrations of MPTP and substrates. In vivo liver and brain studies were conducted using groups of 4 animals treated intraperitoneally with varying doses of MPTP and sacrificed at varying time intervals after treatment. Changes in cytochrome P-450 enzyme contents and activities were determined using standard analytical procedures. MPTP was found from in vitro studies to cause a mixed non-competitive inhibition of cytochrome P-450 dependent ethoxyresorufin O-dealkylase activity with an inhibition constant (Ki) of 0.06 mM. Two binding sites of MPTP to hepatic cytochrome P-450 were found by spectral perturbation studies--the higher affinity site binding about a hundred times more avidly to MPTP than the other. In vivo studies showed a depression of cytochrome P-450 content and activity in a dose-dependent manner. Cytochrome P-450 levels were lowest 3 to 6 hours after treatment with MPTP. MPTP was also found to cause a dose-dependent decrease in the cytochrome P-450 enzyme activities bufuralol hydroxylase (buf) and aryl hydrocarbon hydroxylase (AHH) in the brain. Bufuralol hydroxylase activity was found to be about 2000 times more sensitive than aryl hydrocarbon hydroxylase to the effects of MPTP.(ABSTRACT TRUNCATED AT 250 WORDS)
Shahi
G S
GS
Department of Physiology, Faculty of Medicine, National University of Singapore.
Moochhala
S M
SM
Lee
E J
EJ
Das
N P
NP
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D010300:Parkinson Disease / Q000201:enzymology / Q000209:etiology*; D011725:Pyridines / Q000378:metabolism* / Q000494:pharmacology
D011725:Pyridines; D003577:Cytochrome P-450 Enzyme System; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; C043872:bufuralol 1'-hydroxylase