| Metabolism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in perfused rat liver: involvement of hepatic aldehyde oxidase as a detoxification enzyme. | |
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MedLine Citation:
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PMID: 10772632 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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To elucidate the toxicological relevance of hepatic aldehyde oxidase (AO) as a detoxification enzyme of 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP), we studied the metabolism and the hepatotoxicity of MPTP in intact rat livers exhibiting different AO activities by using a recirculating perfusion method. In the perfusate during a 90-min recirculation of 1 mM MPTP, the perfused liver from Jcl:Wistar rat, a strain showing high AO activity, generated almost equal amounts of 1-methyl-4-phenylpyridinium species (MPP(+)) and 1-methyl-4-phenyl-5,6-dihydro-2-pyridone (MPTP lactam) as major metabolites, together with 4-phenyl-1,2,3, 6-tetrahydropyridine, 1-methyl-4-phenyl-2-pyridone (MP 2-pyridone) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine N-oxide. However, a marked decrease of MPTP lactam as well as MP 2-pyridone and a concomitant increase of MPP(+) were caused by coinfusion of 2-hydroxypyrimidine (2-OH PM), a competitive inhibitor of AO, into Jcl:Wistar rat liver. A quite similar metabolic profile was obtained on perfusion of AO-deficient WKA/Sea rat liver. Rather large amounts of MPP(+) were retained in the liver in all cases, but especially in Jcl:Wistar rat in the presence of 2-OH PM. Lactate dehydrogenase leakage into the perfusate from rat liver perfused with 1 mM MPTP was greater in the strain with lower AO activity, WKA/Sea, than in that with higher AO activity, Jcl:Wistar. Furthermore, inhibition of AO in Jcl:Wistar rat in the presence of 2-OH PM caused an enhancement of lactate dehydrogenase leakage. These results suggest that hepatic AO is a key detoxification enzyme for MPTP. |
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Authors:
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S Yoshihara; K Harada; S Ohta |
Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Drug metabolism and disposition: the biological fate of chemicals Volume: 28 ISSN: 0090-9556 ISO Abbreviation: Drug Metab. Dispos. Publication Date: 2000 May |
Date Detail:
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Created Date: 2000-06-02 Completed Date: 2000-06-02 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 9421550 Medline TA: Drug Metab Dispos Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 538-43 Citation Subset: IM |
Affiliation:
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Institute of Pharmaceutical Sciences, Hiroshima University School of Medicine, Hiroshima, Japan. yosihara@pharm.hiroshima-u.ac.jp |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
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pharmacokinetics* Aldehyde Oxidase Aldehyde Oxidoreductases / metabolism* Animals Biotransformation Chromatography, High Pressure Liquid Dopamine Agents / pharmacokinetics* Drug-Induced Liver Injury / enzymology L-Lactate Dehydrogenase / metabolism Liver / enzymology, metabolism* Male Metabolic Detoxication, Drug / physiology* Rats Rats, Wistar |
| Chemical | |
Reg. No./Substance:
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0/Dopamine Agents; 28289-54-5/1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; EC 1.1.1.27/L-Lactate Dehydrogenase; EC 1.2.-/Aldehyde Oxidoreductases; EC 1.2.3.1/Aldehyde Oxidase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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