Involvement of hepatic aldehyde oxidase in conversion of 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP+) to 1-methyl-4-phenyl-5,6-dihydro-2-pyridone.
To obtain direct evidence of the involvement of aldehyde oxidase (AO), a cytosolic molybdoflavoenzyme, in the metabolism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), we investigated the in vitro metabolism of MPTP and the two-electron-oxidized 1-methyl-4-phenyl-2,3-dihydropyridinium species (MPDP+) by using mouse liver enzyme preparations. Incubation of MPTP with mitochondrial fraction gave exclusively 1-methyl-4-phenylpyridinium (MPP+); this reaction was inhibited by deprenyl, a monoamine oxidase (MAO)-B inhibitor, and KCN. When the mitochondrial fraction was combined with the cytosolic fraction, MPP+ formation was markedly decreased, while a large amount of 1-methyl-4-phenyl-5, 6-dihydro-2-pyridone (MPTP lactam) was newly formed. Incubation of MPDP+ with the cytosolic fraction led to rapid formation of MPTP lactam with concomitant disappearance of the substrate. The cytosol-dependent formation of MPTP lactam was inhibited by known AO inhibitors, such as menadione, norharman, and KCN. The activity of cytosol in MPTP lactam formation was completely duplicated by purified mouse liver AO. These results indicate that AO catalyzes the metabolic conversion of MPDP+, produced from MPTP by MAO-B, to MPTP lactam. This metabolic pathway might be an important detoxification route, averting the formation of toxic MPP+.
Yoshihara
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S
Institute of Pharmaceutical Sciences, Hiroshima University School of Medicine, 1-2-3 Kasumi, Hiroshima, Minami-ku, 734-8551, Japan. yosihara@pharm.hiroshima-u.ac.jp
Ohta
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S
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000378:metabolism; D042931:Aldehyde Oxidase; D000445:Aldehyde Oxidoreductases / Q000378:metabolism*; D000818:Animals; D001711:Biotransformation; D007769:Lactams / Q000378:metabolism*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008930:Mitochondria, Liver / Q000201:enzymology*; D011726:Pyridinium Compounds / Q000378:metabolism*; D011728:Pyridones / Q000378:metabolism*
C116575:1-methyl-4-phenyl-5,6-dihydro-2-pyridone; D007769:Lactams; D011726:Pyridinium Compounds; D011728:Pyridones; C044755:1-methyl-4-phenyl-2,3-dihydropyridinium; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000445:Aldehyde Oxidoreductases; D042931:Aldehyde Oxidase