Disposition of histamine, its metabolites, and pros-methylimidazoleacetic acid in brain regions of rats chronically infused with alpha-fluoromethylhistidine.
Disposition of histamine, its metabolites, and pros-methylimidazoleacetic acid in brain regions of rats chronically infused with alpha-fluoromethylhistidine.
复制标题
长期注射α-氟甲基组氨酸的大鼠脑区域中组胺、其代谢物和前甲基咪唑乙酸的分布。
DOI：
10.1046/j.1471-4159.1996.66052153.x
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发表时间：
1996
影响因子：
4.7
通讯作者：
Morrishow,AM
中科院分区：
文献类型：
--
作者：
Prell,GD;Douyon,E;Sawyer,WF;Morrishow,AM
在哺乳动物的大脑中，已知组胺仅由组胺甲基转移酶（HMT）、甲酰基甲基组胺（t - MH）、甲基咪唑乙酸（t - MIAA）代谢。我们之前的研究表明，氨基丁酸激动剂咪唑乙酸（IAA）和组胺在外周的代谢物存在于大脑中，其浓度在HMT抑制后增加。此外，当大鼠脑室内给予[3H]组胺时，一部分转化为IAA，这一过程因抑制HMT而增加。这些结果表明，大脑具有氧化组胺的能力，但没有显示这一途径是否在生理条件下起作用。为了解决这个问题，我们给大鼠注射了α‐氟甲基组氨酸（α‐FMHis） 4周，α‐氟甲基组氨酸是一种不可逆的组胺合成酶，1‐组氨酸脱羧酶抑制剂。与对照组（未治疗和生理盐水治疗的大鼠）相比，治疗大鼠脑内所有区域的组胺、t - MH和t - MIAA水平均显著降低。与对照组相比，所有区域的t - MIAA >组胺耗竭和t - MH >组胺耗竭与大鼠大脑各区域的组胺周转率相对应。相比之下，IAA的水平和甲基咪唑乙酸（与组胺代谢无关的t - MIAA的异构体）的水平没有变化。结果表明，在大鼠的大脑中，与外周不同，大多数IAA可能通常不是来自组胺。由于大脑中的组胺在一定条件下可以转化为IAA，因此组胺的直接氧化可能是一种条件现象。我们的研究结果也支持了脑组织胺缓慢周转池的存在，并支持了慢性α - FMHis输注作为脑组织胺能系统探测模型的使用。
In mammalian brain, histamine is known to be metabolized solely by histamine methyltransferase (HMT), formingtele‐methylhistamine (t‐MH), thentele‐methylimidazoleacetic acid (t‐MIAA). We previously showed that imidazoleacetic acid (IAA), a GABA agonist, and histamine's metabolite in the periphery, is present in brain where its concentration increased after inhibition of HMT. Also, when [3H]histamine was given intracerebroventricularly to rats, a portion was converted to IAA, a process increased by inhibition of HMT. These results indicated that brain has the capacity to oxidize histamine but did not show whether this pathway is operative under physiological conditions. To address this question, rats were infused for >4 weeks with α‐fluoromethylhistidine (α‐FMHis), an irreversible inhibitor of histamine's synthetic enzyme,l‐histidine decarboxylase. Compared with controls (untreated and saline‐treated rats), brain levels of histamine, t‐MH, and t‐MIAA in all regions were markedly reduced in treated rats. As a percentage of controls, depletion of t‐MIAA > t‐MH > histamine in all regions, and regional depletions of histamine corresponded to its turnover rates in regions of rat brain. In contrast, levels of IAA were unchanged as were levels ofpros‐methylimidazoleacetic acid, an isomer of t‐MIAA unrelated to histamine metabolism. Results suggest that in brains of rats, unlike in the periphery, most IAA may not normally derive from histamine. Because histamine in brain can be converted to IAA under certain conditions, direct oxidation of histamine may be a conditional phenomenon. Our results also support the existence of a very slow turnover pool of brain histamine and use of chronic α‐FMHis infusion as a model to probe the histaminergic system in brain.