Yang S C, Johannessen J N, Markey S P
Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, Maryland 20892.
Chem Res Toxicol. 1988 Jul-Aug;1(4):228-33. doi: 10.1021/tx00004a007.
The distribution, identification, and binding of [phenyl-14C]- or [methyl-14C]MPTP metabolites have been determined in brains of mouse and monkey exposed to toxic doses of MPTP. The distribution of radiolabeled metabolites was heterogeneous, with levels of MPP+ 1-100 mumol/L in dissected and homogenized monkey brain tissues. MPP+ constituted greater than 98% of all tissue radioactivity remaining at 1-3 days in the monkey and was identified in both cortical and striatal tissue. The relevance of the 2% of unextractable ("bound") radiolabeled metabolite was assessed in mouse brain by using pargyline or mazindol pretreatments which block dopamine depletion. The amount of binding increased rather than decreased when [phenyl-14C]MPTP was used along with pargyline or mazindol but was unchanged when [methyl-14C]MPTP was employed. This demonstrates that bound metabolites are inversely correlated to neurotoxicity as well as being N-demethylated. Two extractable metabolites, demethylated MPTP (PTP) and 1-methyl-4-phenyl-2-pyridone, were found at 30-min survival times in mouse brain and probably derive from peripheral metabolism of MPTP. At 4 h, mouse brain profiles of extractable metabolites resembled those from monkey brain, containing MPP+ as the predominant (greater than 90%) constituent. The similarity of MPP+ concentrations in mouse and monkey brain homogenates with those concentrations of MPP+ known to produce biological effects in vitro, along with the inverse relationship between bound metabolites and neurotoxicity, supports the intermediacy of MPP+ as the operative neurotoxin.
已测定了暴露于毒性剂量MPTP的小鼠和猴脑中[苯基-¹⁴C]-或[甲基-¹⁴C]MPTP代谢物的分布、鉴定及结合情况。放射性标记代谢物的分布是不均匀的，在解剖并匀浆的猴脑组织中MPP⁺水平为1 - 100 μmol/L。在猴中，MPP⁺占1 - 3天所有残留组织放射性的98%以上，且在皮质和纹状体组织中均被鉴定出。通过使用能阻断多巴胺耗竭的帕吉林或吗茚酮预处理，在小鼠脑中评估了2%不可提取（“结合”）放射性标记代谢物的相关性。当[苯基-¹⁴C]MPTP与帕吉林或吗茚酮一起使用时，结合量增加而非减少，但当使用[甲基-¹⁴C]MPTP时结合量不变。这表明结合代谢物与神经毒性呈负相关，并且是N - 去甲基化的。在小鼠脑存活30分钟时发现了两种可提取的代谢物，去甲基化MPTP（PTP）和1 - 甲基 - 4 - 苯基 - 2 - 吡啶酮，它们可能源自MPTP的外周代谢。在4小时时，小鼠脑可提取代谢物的图谱类似于猴脑的图谱，以MPP⁺作为主要（大于90%）成分。小鼠和猴脑匀浆中MPP⁺浓度与已知在体外产生生物学效应的MPP⁺浓度相似，以及结合代谢物与神经毒性之间的负相关关系，支持了MPP⁺作为起作用的神经毒素的中间地位。
