Inhibition of tyrosine hydroxylation in tissue slices of the rat striatum by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Inhibition of tyrosine hydroxylation in tissue slices of the rat striatum by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
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1-甲基-4-苯基-1,2,3,6-四氢吡啶抑制大鼠纹状体组织切片中酪氨酸羟基化
DOI：
10.1016/0006-8993(85)91631-2
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发表时间：
1985
期刊：
影响因子：
2.9
通讯作者：
T. Nagatsu
中科院分区：
文献类型：
--
作者：
Y. Hirata;T. Nagatsu
1-甲基-4-苯基-1，2，3，6-四氢吡啶是人和灵长类动物的黑质纹状体神经毒素，在10−5M时，可抑制大鼠纹状体和伏隔核组织切片中酪氨酸羟化为多巴胺合成的限速步骤3，4-二氢苯丙氨酸。多巴胺摄取抑制剂诺米芬辛逆转了这种抑制作用，但多巴胺受体拮抗剂舒必利不影响这种抑制作用。10−5M的MPTP在体外对纯化的酪氨酸羟基酶和二氢蝶啶还原酶均无抑制作用。MPTP孵育的纹状体脑片中总生物蝶呤水平无明显变化，但四氢生物蝶呤水平降低。这些结果提示MPTP可能通过抑制二氢蝶呤还原酶而抑制酪氨酸羟化酶在原位的多巴胺合成。
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a nigrostriatal neurotoxin in humans and primates, at 10−5M inhibited hydroxylation of tyrosine to 3,4-dihydrophenylalanine (DOPA), the rate-limiting step of dopamine synthesis, in tissue slices of the striatum and nucleus accumbens of the rat. Nomifensine, an inhibitor of dopamine uptake, reversed the inhibition but sulpiride, a dopamine receptor antagonist, did not affect the inhibition. MPTP at 10−5M inhibited neither the purified tyrosine hydroxylase nor dihydropteridine reductase in vitro. The level of total biopterin did not change significantly, but the tetrahydrobiopterin level was decreased in the striatal slices incubated in the presence of MPTP. These results suggest that MPTP inhibits dopamine synthesis in situ at the tyrosine hydroxylase step probably through inhibition of dihydropteridine reductase.