Abstract
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-tetrahydropyridineN-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.
Footnotes
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Send reprint requests to: Dr. S. Yoshihara, Institute of Pharmaceutical Sciences, Hiroshima University School of Medicine, 1–2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan. E-mail:yosihara{at}pharm.hiroshima-u.ac.jp
- Abbreviations used are::
- MPTP
- 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine
- MPP+
- 1-methyl-4-phenylpyridinium species
- MPDP+
- 1-methyl-4-phenyl-2,3-dihydropyridinium species
- MAO-B
- monoamine oxidase-B
- PTP
- 4-phenyl-1,2,3,6-tetrahydropyridine
- MPTP lactam
- 1-methyl-4-phenyl-5,6-dihydro-2-pyridone
- MP 2-pyridone
- 1-methyl-4-phenyl-2-pyridone
- MPTP N-oxide
- 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine N-oxide
- 4-PP,4-phenylpyridine
- P450, cytochrome P-450
- FMO
- flavin-containing monooxygenase
- AO
- aldehyde oxidase
- 2-OH PM
- 2-hydroxypyrimidine
- LDH
- lactate dehydrogenase
- Received October 29, 1999.
- Accepted January 27, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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