Elevated baseline serum glutamate as a pharmacometabolomic biomarker for acamprosate treatment outcome in alcohol-dependent subjects.
Elevated baseline serum glutamate as a pharmacometabolomic biomarker for acamprosate treatment outcome in alcohol-dependent subjects.
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DOI：
10.1038/tp.2015.120
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发表时间：
2015-08-18
影响因子：
6.8
通讯作者：
Choi DS
中科院分区：
文献类型：
--
作者：
Nam HW;Karpyak VM;Hinton DJ;Geske JR;Ho AM;Prieto ML;Biernacka JM;Frye MA;Weinshilboum RM;Choi DS
自2004年美国食品和药物管理局批准阿卡米松用于治疗酒精使用障碍(AUDS)以来，该药物一直被广泛使用。虽然氨基己酸酯的详细分子机制尚不清楚，但已基本知道氨基己酸酯可抑制大脑中的谷氨酸活动。然而，AUD是一种复杂的异质性疾病。因此，需要生物标记物将这种药物开给那些有最高可能性呈阳性反应的患者。为了确定氨基己酸酯反应的药物代谢组学生物标记物，我们使用了120名酒精依赖受试者的血清样本，其中包括71名应答者(持续戒酒)和49名无应答者(任何酒精使用)，在氨基己酸酯治疗12周期间。值得注意的是，应答者的基线血清谷氨酸水平显著高于无应答者。重要的是，应答者的血清谷氨酸水平在氨基己酸酯治疗后恢复正常，而无应答者的谷氨酸水平没有显著变化。随后的动物模型功能研究显示，在没有酒精的情况下，氨基己酸酯激活谷氨酰胺合成酶，谷氨酰胺合成酶从谷氨酸和氨中合成谷氨酰胺。这些结果表明，对于那些基线血清谷氨酸水平在应答者中升高的人，氨基己酸酯降低了血清谷氨酸水平。综上所述，我们的研究结果表明，基线血清谷氨酸水平升高是与AUD阳性反应相关的潜在生物标志物，这是开发个性化治疗AUD的重要一步。
Acamprosate has been widely used since the Food and Drug Administration approved the medication for treatment of alcohol use disorders (AUDs) in 2004. Although the detailed molecular mechanism of acamprosate remains unclear, it has been largely known that acamprosate inhibits glutamate action in the brain. However, AUD is a complex and heterogeneous disorder. Thus, biomarkers are required to prescribe this medication to patients who will have the highest likelihood of responding positively. To identify pharmacometabolomic biomarkers of acamprosate response, we utilized serum samples from 120 alcohol-dependent subjects, including 71 responders (maintained continuous abstinence) and 49 non-responders (any alcohol use) during 12 weeks of acamprosate treatment. Notably, baseline serum glutamate levels were significantly higher in responders compared with non-responders. Importantly, serum glutamate levels of responders are normalized after acamprosate treatment, whereas there was no significant glutamate change in non-responders. Subsequent functional studies in animal models revealed that, in the absence of alcohol, acamprosate activates glutamine synthetase, which synthesizes glutamine from glutamate and ammonia. These results suggest that acamprosate reduces serum glutamate levels for those who have elevated baseline serum glutamate levels among responders. Taken together, our findings demonstrate that elevated baseline serum glutamate levels are a potential biomarker associated with positive acamprosate response, which is an important step towards development of a personalized approach to treatment for AUD.