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.
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.
Yoshihara
S
S
Institute of Pharmaceutical Sciences, Hiroshima University School of Medicine, Hiroshima, Japan. yosihara@pharm.hiroshima-u.ac.jp
Harada
K
K
Ohta
S
S
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000493:pharmacokinetics*; D042931:Aldehyde Oxidase; D000445:Aldehyde Oxidoreductases / Q000378:metabolism*; D000818:Animals; D001711:Biotransformation; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology; D002851:Chromatography, High Pressure Liquid; D015259:Dopamine Agents / Q000493:pharmacokinetics*; D008658:Inactivation, Metabolic / Q000502:physiology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar
D015259:Dopamine Agents; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D007770:L-Lactate Dehydrogenase; D000445:Aldehyde Oxidoreductases; D042931:Aldehyde Oxidase