Williams A C, Cartwright L S, Ramsden D B
Division of Neurosciences, University of Birmingham, Edgbaston, Birmingham.
QJM. 2005 Mar;98(3):215-26. doi: 10.1093/qjmed/hci027.
Parkinson's disease may be a disease of autointoxication. N-methylated pyridines (e.g. MPP+) are well-established dopaminergic toxins, and the xenobiotic enzyme nicotinamide N-methyltransferase (NNMT) can convert pyridines such as 4-phenylpyridine into MPP+, using S-adenosyl methionine (SAM) as the methyl donor. NNMT has recently been shown to be present in the human brain, a necessity for neurotoxicity, because charged compounds cannot cross the blood-brain barrier. Moreover, it is present in increased concentration in parkinsonian brain. This increase may be part genetic predisposition, and part induction, by excessive exposure to its substrates (particularly nicotinamide) or stress. Elevated enzymic activity would increase MPP+-like compounds such as N-methyl nicotinamide at the same time as decreasing intraneuronal nicotinamide, a neuroprotectant at several levels, creating multiple hits, because Complex 1 would be poisoned and be starved of its major substrate NADH. Developing xenobiotic enzyme inhibitors of NNMT for individuals, or dietary modification for the whole population, could be an important change in thinking on primary and secondary prevention.
帕金森病可能是一种自体中毒性疾病。N-甲基吡啶（如MPP+）是公认的多巴胺能毒素，而异生物质酶烟酰胺N-甲基转移酶（NNMT）可以利用S-腺苷甲硫氨酸（SAM）作为甲基供体，将4-苯基吡啶等吡啶转化为MPP+。最近研究表明，NNMT存在于人类大脑中，这是神经毒性的必要条件，因为带电化合物无法穿过血脑屏障。此外，它在帕金森病患者大脑中的浓度升高。这种升高可能部分是由于遗传易感性，部分是由于过度暴露于其底物（特别是烟酰胺）或压力导致的诱导作用。酶活性升高会在降低神经元内烟酰胺（一种在多个层面具有神经保护作用的物质）的同时，增加MPP+样化合物，如N-甲基烟酰胺，从而造成多重打击，因为复合物I会中毒并缺乏其主要底物NADH。为个体开发NNMT的异生物质酶抑制剂，或对整个人群进行饮食调整，可能是在一级和二级预防方面思维的重要转变。
