研究者們發(fā)現(xiàn)抗瘧疾藥奎寧能夠阻斷細(xì)胞吸收必需氨基酸色氨酸的功能,，該發(fā)現(xiàn)可以解釋服用奎寧引起的很多副作用,。這些發(fā)現(xiàn)一旦被確定，它就能證明服用色氨酸補(bǔ)充劑是一種提高奎寧藥效的簡(jiǎn)單而經(jīng)濟(jì)的方法,。
奎寧是一種非常常用的抗瘧疾藥,，即便是現(xiàn)在，奎寧對(duì)抗瘧原蟲(chóng)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,，例如惡心,、頭痛以及視線(xiàn)模糊。為了搞清這些問(wèn)題,，諾丁漢大學(xué)的Simon Avery及其同事們利用酵母的基因組,，檢測(cè)了奎寧對(duì)6000種酵母基因突變的影響，每種突變都缺失酵母6000個(gè)基因中的一種,。盡管與人類(lèi)的差別巨大,，但在細(xì)胞水平上酵母是一種檢測(cè)化合物和小分子藥物常用且成熟的前沿檢測(cè)手段。
他們通過(guò)篩選發(fā)現(xiàn),，色氨酸缺陷型菌株對(duì)奎寧的毒性更為敏感,，由此他們確定出一種色氨酸轉(zhuǎn)運(yùn)子是奎寧的關(guān)鍵靶標(biāo)（酵母本身不能合成色氨酸，它們依賴(lài)于外源色氨酸,，如果色氨酸轉(zhuǎn)運(yùn)被阻斷,，就會(huì)導(dǎo)致死亡）。
這項(xiàng)發(fā)現(xiàn)符合營(yíng)養(yǎng)不良患者對(duì)奎寧反應(yīng)更為強(qiáng)烈的情況,。人類(lèi)也不能自身合成色氨酸,，但與酵母不同，人類(lèi)可以通過(guò)飲食獲取,，肉類(lèi)中色氨酸含量豐富,，在薯類(lèi)食物中則很少，而薯類(lèi)又是瘧疾盛行的熱帶地區(qū)的主要糧食作物。假如奎寧能夠大量減少色氨酸的攝入量,，那這種藥物對(duì)原本就缺乏色氨酸的人群非常危險(xiǎn),。
該論文作者還指出，色氨酸是大腦化合物血清素的前體,，它非常重要,，因此奎寧引起的色氨酸缺乏加劇可以解釋為什么奎寧的很多副作用都發(fā)生在頭部。他們還指出,，盡管尚不清楚色氨酸是否會(huì)影響奎寧對(duì)瘧原蟲(chóng)的療效,，但奎寧的這類(lèi)副作用可以簡(jiǎn)單的通過(guò)在飲食中添加色氨酸補(bǔ)充劑來(lái)預(yù)防。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
