Characterization of hepatic microsomal metabolism as an in vivo detoxication pathway of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a selective neurotoxin to the nigrostriatal dopaminergic neurons, has been shown to be metabolized by microsomal flavin-containing monooxygenase (FMO) to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine N-oxide and by cytochrome (cyt.) P-450 to 4-phenyl-1,2,3,6-tetrahydropyridine in the liver. The present study was conducted to determine whether and to what extent each of these metabolic processes would function as the detoxication pathway(s) of MPTP. Administration of either MPTP metabolites, MPTP N-oxide or 4-phenyl-1,2,3,6-tetrahydropyridine, to mice resulted in no significant reductions in striatal dopamine and its metabolites. Pretreatment of mice with alternate substrate of FMO, N-methylmercaptoimidazole or thiobenzamide significantly (P less than .001 to .05) enhanced MPTP-induced reductions in striatal dopamine and its metabolites. In contrast, neither pretreatments with cyt. P-450 inhibitors, SKF-525A (2-diethylaminoethyl-2,2-diphenyl-valerate), quinidine and cimetidine nor with the inducers, phenobarbital and 3-methyl-cholanthrene altered the neurotoxic effects of MPTP. The rate of clearance (Vmax/Km) of N-oxygenation by hepatic microsomes from intact mice was 32 times greater than that of N-demethylation. Although phenobarbital treatment increased Vmax/Km of N-demethylation by 100%, it was still 10 times lower than that of N-oxygenation. Thus, the different responsivenesses of MPTP-treated mice to alternate substrates of FMO and cyt. P-450 modulators appear to come from the difference in the rate of metabolism between N-oxygenation and N-demethylation of MPTP.(ABSTRACT TRUNCATED AT 250 WORDS)
Chiba
K
K
Division of Clinical Pharmacology, National Medical Center, Tokyo, Japan.
Kubota
E
E
Miyakawa
T
T
Kato
Y
Y
Ishizaki
T
T
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D006719:Homovanillic Acid / Q000378:metabolism; D008658:Inactivation, Metabolic; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D010105:Oxygenases / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D011725:Pyridines / Q000493:pharmacokinetics*
D011725:Pyridines; D015102:3,4-Dihydroxyphenylacetic Acid; D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); D004298:Dopamine; D006719:Homovanillic Acid; D010634:Phenobarbital