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Characterization of hepatic microsomal metabolism as an in vivo detoxication pathway of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice.
J Pharmacol Exp Ther. 1988 Sep; 246(3):1108-15.JP

Abstract

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)

Authors+Show Affiliations

Division of Clinical Pharmacology, National Medical Center, Tokyo, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

3262153

Citation

Chiba, K, et al. "Characterization of Hepatic Microsomal Metabolism as an in Vivo Detoxication Pathway of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in Mice." The Journal of Pharmacology and Experimental Therapeutics, vol. 246, no. 3, 1988, pp. 1108-15.
Chiba K, Kubota E, Miyakawa T, et al. Characterization of hepatic microsomal metabolism as an in vivo detoxication pathway of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice. J Pharmacol Exp Ther. 1988;246(3):1108-15.
Chiba, K., Kubota, E., Miyakawa, T., Kato, Y., & Ishizaki, T. (1988). Characterization of hepatic microsomal metabolism as an in vivo detoxication pathway of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice. The Journal of Pharmacology and Experimental Therapeutics, 246(3), 1108-15.
Chiba K, et al. Characterization of Hepatic Microsomal Metabolism as an in Vivo Detoxication Pathway of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in Mice. J Pharmacol Exp Ther. 1988;246(3):1108-15. PubMed PMID: 3262153.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Characterization of hepatic microsomal metabolism as an in vivo detoxication pathway of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice. AU - Chiba,K, AU - Kubota,E, AU - Miyakawa,T, AU - Kato,Y, AU - Ishizaki,T, PY - 1988/9/1/pubmed PY - 1988/9/1/medline PY - 1988/9/1/entrez SP - 1108 EP - 15 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 246 IS - 3 N2 - 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) SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/3262153/Characterization_of_hepatic_microsomal_metabolism_as_an_in_vivo_detoxication_pathway_of_1_methyl_4_phenyl_1236_tetrahydropyridine_in_mice_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=3262153 DB - PRIME DP - Unbound Medicine ER -