Studies on the cytochrome P-450 catalyzed ring alpha-carbon oxidation of the nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).
Studies on the cytochrome P-450 catalyzed ring alpha-carbon oxidation of the nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).
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细胞色素 P-450 催化黑质纹状体毒素 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 环 α-碳氧化的研究。
DOI：
10.1021/tx00017a006
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发表时间：
1990
影响因子：
4.1
通讯作者：
CastagnoliJr,N
中科院分区：
文献类型：
--
作者：
Ottoboni,S;Carlson,TJ;Trager,WF;Castagnoli,K;CastagnoliJr,N
体外代谢研究已确定，大鼠肝细胞色素 P-450IIB1 和 P-450IA1（而非兔肝细胞色素 P-450IIB4）能够催化帕金森病诱导神经毒素 L-甲基-4-苯基-1, 2, 3, 6-四氢吡啶 (MPTP) 氧化成相应的二氢吡啶鎓 (MPDP+) 和吡啶鎓 (MPP+) 物质。使用最有效的同工酶细胞色素 P-450IA1 进行的动力学实验表明，反应以中等速度 [Vmax= 20.1 nmol/(min-nmol of P-450IA1)] 和高 K „(0.87 mM) 进行。此外，动力学氘同位素效应测量提供的 DV 和®(V/K) 值分别为 2.99 和 1.04。单胺氧化酶 B (MAO-B) 催化反应的相应值（分别为 4.37 和 9.35）表明这些酶通过不同途径催化 MPTP 的环碳氧化，或者先前提出的两种酶系统产生铵自由基中间体的初始单电子转移在 MAO-B 情况下是可逆的，在细胞色素 P-450IA1 情况下是不可逆的。
In vitro metabolic studies have established that rat liver cytochromes P-450IIB1 and P-450IA1 but not rabbit liver cytochrome P-450IIB4 catalyze the oxidationof the Parkinsonian inducing neurotoxin l-methyl-4-phenyl-l, 2, 3, 6-tetrahydropyridine (MPTP) to the corresponding dihydropyridinium (MPDP+) and pyridinium (MPP+) species. Kinetic experiments with the most effective isozyme, cytochrome P-450IA1, indicate that the reaction proceeds at a moderate velocity [Vmax= 20.1 nmol/(min-nmol ofP-450IA1)] and high K „(0.87 mM). Futhermore, kinetic deuterium isotope effect measurements provided DV and®(V/K) values of 2.99 and 1.04, re-spectively. A comparison with the corresponding values for the monoamine oxidase B (MAO-B) catalyzed reaction (4.37 and 9.35, respectively) suggests that either these enzymes catalyze the ring-carbon oxidation of MPTP by different pathways or that the initial one-electron transfer to generate an aminium radical intermediate previously proposed for both enzyme systems is reversible in the case of MAO-B and irreversiblein the case of cytochrome P-450IA1.