Inhibitors of histamine methylation in brain promote formation of imidazoleacetic acid, which interacts with GABA receptors.
Inhibitors of histamine methylation in brain promote formation of imidazoleacetic acid, which interacts with GABA receptors.
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大脑中组胺甲基化的抑制剂促进咪唑乙酸的形成，咪唑乙酸与 GABA 受体相互作用。
DOI：
10.1046/j.1471-4159.1997.68010142.x
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发表时间：
1997
影响因子：
4.7
通讯作者：
Lee,WS
中科院分区：
文献类型：
--
作者：
Prell,GD;Morrishow,AM;Duoyon,E;Lee,WS
在大脑中，咪唑乙酸（IAA）的前体尚不清楚，它是gaba受体拮抗剂，但也是gaba受体拮抗剂。在外周，IAA来源于组胺的氧化。但在大脑中，组胺被认为仅由组胺甲基转移酶（HMT）、形成远端甲基组胺（t - MH）和远端甲基咪唑乙酸（t - MIAA）代谢。我们发现[3H]组胺（脑室内）可以在大鼠大脑中转化为IAA，这一过程通过抑制HMT而增加。这表明大脑可以氧化组胺，并提示如果HMT活性降低，内源性组胺也可能被氧化。在大鼠大脑皮层中，我们检测了以下HMT抑制剂（mg/kg i.p.）的作用：甲托林（10），他克林（10），伐尔克林（10,30）和蛇的碱（1,2）。Tacrine是一个有效的抑制剂（Ki ~ 22 nM）。为了测量含有HMT抑制剂的组织中的组胺，我们开发了一种气相色谱-质谱法。2 h后，所有药物均降低内源性t - MH和t - MIAA水平，升高组胺和IAA水平。我们的研究结果表明，抑制HMT促进大脑中组胺的氧化，可能是通过将组胺分流到另一种代谢途径。IAA的形成为脑内组胺能和gaba能系统之间的相互作用提供了一种新的途径。当使用HMT抑制剂探测脑组胺功能时，应考虑IAA的积累。
In brain, the precursor of imidazoleacetic acid (IAA), a GABAAagonist but a GABACantagonist, is not known. In the periphery, IAA derives from oxidation of histamine. But in brain, histamine is thought to be metabolized solely by histamine methyltransferase (HMT), formingtele‐methylhistamine (t‐MH) andtele‐methylimidazoleacetic acid (t‐MIAA). We showed that [3H]histamine (intracerebroventricularly) could be converted to IAA in brains of rats, a process increased by inhibition of HMT. This demonstrated that brain can oxidize histamine and suggested that endogenous histamine might also be oxidized if HMT activity were reduced. We examined, in rat cerebral cortex, effects of the following HMT inhibitors (mg/kg i.p.): metoprine (10), tacrine (10), velnacrine (10, 30), and physostigmine (1, 2). Tacrine was a potent inhibitor (Ki∼ 22 nM). To measure histamine in tissue that contained HMT inhibitors, we developed a gas chromatography‐mass spectrometry method. After 2 h, all drugs reduced endogenous levels of t‐MH and t‐MIAA and increased levels of histamine and IAA. Our results show that inhibition of HMT promotes oxidation of histamine in brain, probably by shunting histamine to an alternative metabolic pathway. Formation of IAA provides a novel interaction between histaminergic and GABAergic systems in brain. Accumulation of IAA should be considered when inhibitors of HMT are used to probe brain histamine function.