Sablin S O, Krueger M J, Bachurin S O, Solyakov L S, Efange S M, Singer T P
Department of Biochemistry and Biophysics, University of California, San Francisco.
J Neurochem. 1994 May;62(5):2012-6. doi: 10.1046/j.1471-4159.1994.62052012.x.
1-Methyl-4-benzyl-1,2,3,6-tetrahydropyridine (MBzTP), an analogue of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, despite its rapid oxidation by monoamine oxidase B (MAO B), is not neurotoxic. The pyridinium expected to arise from the four-electron oxidation of MBzTP inhibits mitochondrial respiration and the oxidation of NADH in inner membranes and is only moderately less inhibitory than 1-methyl-4-phenylpyridinium. It is also a competitive inhibitor of dopamine uptake by the dopamine transporter and hence likely to be taken up into neurons, despite its relatively high Ki value (Ki = 21 microM). Incubation of MBzTP with purified MAO B yields first the dihydropyridinium form, then a mixture of the pyridinium form and another unidentified product, in proportions that depend on the concentrations of MAO B and oxygen. At low MAO B concentration and moderate oxygen concentration, nonenzymatic formation of the unidentified product predominates. The lack of neurotoxicity of MBzTP appears to be due to the oxidative destruction of the dihydropyridine and consequent failure of accumulation of 1-methyl-4-benzylpyridinium.
1-甲基-4-苄基-1,2,3,6-四氢吡啶（MBzTP）是神经毒素1-甲基-4-苯基-1,2,3,6-四氢吡啶的类似物，尽管它能被单胺氧化酶B（MAO B）快速氧化，但却没有神经毒性。预计MBzTP经四电子氧化产生的吡啶鎓会抑制线粒体呼吸以及内膜中NADH的氧化，其抑制作用仅比1-甲基-4-苯基吡啶鎓略弱。它还是多巴胺转运体摄取多巴胺的竞争性抑制剂，因此尽管其Ki值相对较高（Ki = 21微摩尔），但仍可能被神经元摄取。将MBzTP与纯化的MAO B一起孵育，首先会产生二氢吡啶鎓形式，然后是吡啶鎓形式与另一种未鉴定产物的混合物，其比例取决于MAO B和氧气的浓度。在低MAO B浓度和中等氧气浓度下，未鉴定产物的非酶促形成占主导。MBzTP缺乏神经毒性似乎是由于二氢吡啶的氧化破坏以及随后1-甲基-4-苄基吡啶鎓积累的失败。
