研究者们发现抗疟疾药奎宁能够阻断细胞吸收必需氨基酸色氨酸的功能,该发现可以解释服用奎宁引起的很多副作用。这些发现一旦被确定,它就能证明服用色氨酸补充剂是一种提高奎宁药效的简单而经济的方法。
奎宁是一种非常常用的抗疟疾药,即便是现在,奎宁对抗疟原虫的基本模式以及引起有害副作用的原因仍有很多未研究清楚,例如恶心、头痛以及视线模糊。为了搞清这些问题,诺丁汉大学的Simon Avery及其同事们利用酵母的基因组,检测了奎宁对6000种酵母基因突变的影响,每种突变都缺失酵母6000个基因中的一种。尽管与人类的差别巨大,但在细胞水平上酵母是一种检测化合物和小分子药物常用且成熟的前沿检测手段。
他们通过筛选发现,色氨酸缺陷型菌株对奎宁的毒性更为敏感,由此他们确定出一种色氨酸转运子是奎宁的关键靶标(酵母本身不能合成色氨酸,它们依赖于外源色氨酸,如果色氨酸转运被阻断,就会导致死亡)。
这项发现符合营养不良患者对奎宁反应更为强烈的情况。人类也不能自身合成色氨酸,但与酵母不同,人类可以通过饮食获取,肉类中色氨酸含量丰富,在薯类食物中则很少,而薯类又是疟疾盛行的热带地区的主要粮食作物。假如奎宁能够大量减少色氨酸的摄入量,那这种药物对原本就缺乏色氨酸的人群非常危险。
该论文作者还指出,色氨酸是大脑化合物血清素的前体,它非常重要,因此奎宁引起的色氨酸缺乏加剧可以解释为什么奎宁的很多副作用都发生在头部。他们还指出,尽管尚不清楚色氨酸是否会影响奎宁对疟原虫的疗效,但奎宁的这类副作用可以简单的通过在饮食中添加色氨酸补充剂来预防。(生物谷Bioon.com)
生物谷推荐原始出处:
J. Biol. Chem., Vol. 284, Issue 27, 17968-17974, July 3, 2009
The Antimalarial Drug Quinine Disrupts Tat2p-mediated Tryptophan Transport and Causes Tryptophan Starvation*
Combiz Khozoie, Richard J. Pleass1, and Simon V. Avery2
From the From the School of Biology, Institute of Genetics, University of Nottingham, University Park, Nottingham NG7 2RD, United Kingdom
Quinine is a major drug of choice for the treatment of malaria. However, the primary mode of quinine action is unclear, and its efficacy is marred by adverse reactions among patients. To help address these issues, a genome-wide screen for quinine sensitivity was carried out using the yeast deletion strain collection. Quinine-sensitive mutants identified in the screen included several that were defective for tryptophan biosynthesis (trp strains). This sensitivity was confirmed in independent assays and was suppressible with exogenous Trp, suggesting that quinine caused Trp starvation. Accordingly, quinine was found to inhibit [3H]Trp uptake by cells, and the quinine sensitivity of a trp1 mutant could be rescued by overexpression of Trp permeases, encoded by TAT1 and TAT2. The site of quinine action was identified specifically as the high affinity Trp/Tyr permease, Tat2p, with which quinine associated in a Trp-suppressible manner. A resultant action also on Tyr levels was reflected by the Tyr-suppressible quinine hypersensitivity of an aro7 deletion strain, which is auxotrophic for Tyr (and Phe). The present genome-wide dataset provides an important resource for discovering modes of quinine toxicity. That potential was validated with our demonstration that Trp and Tyr uptake via Tat2p is a major target of cellular quinine toxicity. The results also suggest that dietary tryptophan supplements could help to avert the toxic effects of quinine.