TY - JOUR T1 - 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 JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 538 LP - 543 VL - 28 IS - 5 AU - Shin'ichi Yoshihara AU - Keisuke Harada AU - Shigeru Ohta Y1 - 2000/05/01 UR - http://dmd.aspetjournals.org/content/28/5/538.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -