Naoi M, Dostert P, Yoshida M, Nagatsu T
Department of Biosciences, Nagoya Institute of Technology, Japan.
Adv Neurol. 1993;60:212-7.
N-Methylation of dopamine-derived 6,7-dihydroxyisoquinolines produces compounds whose chemical structures are similar to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). N-Methylation of 1,2,3,4-tetrahydroisoquinoline was proved by in vitro experiments using human brain homogenate as an enzyme source. By in vivo microdialysis in rat brains, N-methylation of 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolines (salsolinols) was also demonstrated. Among the brain regions examined, the activity of N-methylation was the highest in the substantia nigra. N-methyl-1,2,3,4-tetrahydroisoquinoline was oxidized to produce N-methyl-isoquinolinium ion by type A and type B monoamine oxidase prepared from human brain synaptosomal mitochondria. The structure of the oxidized isoquinoline is similar to that of 1-methyl-4-phenylpyridinium ion, a potent dopaminergic neurotoxin. These results indicate that these isoquinolines produced in or around dopamine neurons are N-methylated especially in substantia nigra and may be further oxidized by monoamine oxidase to produce ions. This biosynthesis pathway is quite similar to the oxidative synthesis of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. N-Methylation and oxidation of isoquinolines or other endogenous compounds may be involved in the pathogenesis of Parkinson's disease.
多巴胺衍生的6,7 - 二羟基异喹啉的N - 甲基化产生的化合物，其化学结构类似于1 - 甲基 - 4 - 苯基 - 1,2,3,6 - 四氢吡啶（MPTP）。以人脑匀浆作为酶源的体外实验证明了1,2,3,4 - 四氢异喹啉的N - 甲基化。通过大鼠脑内微透析实验，也证实了1 - 甲基 - 6,7 - 二羟基 - 1,2,3,4 - 四氢异喹啉（萨索林醇）的N - 甲基化。在所检测的脑区中，黑质的N - 甲基化活性最高。由人脑突触体线粒体制备的A型和B型单胺氧化酶可将N - 甲基 - 1,2,3,4 - 四氢异喹啉氧化生成N - 甲基异喹啉鎓离子。氧化后的异喹啉结构类似于强效多巴胺能神经毒素1 - 甲基 - 4 - 苯基吡啶鎓离子。这些结果表明，在多巴胺神经元内或其周围产生的这些异喹啉尤其在黑质中发生N - 甲基化，并可能被单胺氧化酶进一步氧化生成离子。这种生物合成途径与1 - 甲基 - 4 - 苯基 - 1,2,3,6 - 四氢吡啶的氧化合成非常相似。异喹啉或其他内源性化合物的N - 甲基化和氧化可能参与帕金森病的发病机制。
