Fructose and carbonyl metabolites as endogenous toxins
Fructose and carbonyl metabolites as endogenous toxins
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DOI：
10.1016/j.cbi.2008.10.011
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发表时间：
2009-03-16
影响因子：
5.1
通讯作者：
O'Brien, P. J.
中科院分区：
文献类型：
--
作者：
Lee, O.;Bruce, W. R.;O'Brien, P. J.
饮食中果糖的摄入是导致肥胖和脂肪肝（肝性脂肪变性）的环境因素之一。对于肝脂肪变性发展为更严重的非酒精性脂肪变性（NASH），提出了一种双重打击假说，第一次打击是肝脂肪变性，第二次打击是由活性氧（ROS）形成引起的炎症和相关氧化应激。此外，果糖喂养的大鼠会产生胰岛素抵抗，血清中糖酵解代谢物甲基乙二醛的水平也会升高。之前我们报道过，乙二醛诱导的肝细胞毒性可归因于线粒体毒性，因为低剂量的非细胞毒性H2O2降低了线粒体膜电位，细胞毒性增加了几个数量级（肝细胞炎症模型）。在这项研究中，我们评估了果糖对肝细胞的毒性，并研究了所涉及的分子细胞毒性机制。果糖本身仅在1.5 M时具有毒性，而如果肝细胞连续暴露于葡萄糖和葡萄糖氧化酶产生的无细胞毒性剂量的H2O2，则12 mM可在2 h内导致50%的细胞死亡。细胞毒性机制涉及氧化应激，因为ROS和H2O2的形成先于细胞毒性，而自由基清除剂、脂质抗氧化剂和ROS清除剂可预防细胞毒性。有人提出，高效的芬顿衍生活性氧催化果糖的氧化，特别是其羰基代谢物乙醇醛，二羟基丙酮，甘油醛。碳自由基和乙二醛的形成损害了细胞对H2O2的抵抗力。2008爱思唯尔爱尔兰有限公司版权所有。
Dietary fructose consumption is one of the environmental factors contributing to the development of obesity and a fatty liver (hepatic steatosis). A two-hit hypothesis has been proposed for progression of hepatic steatosis to the more serious non-alcoholic steatosis (NASH), with the first hit being hepatic steatosis, and the second hit being inflammation and associated oxidative stress caused by reactive oxygen species (ROS) formation. As well, fructose-fed rats develop insulin resistance and serum levels of methylglyoxal, a glycolytic metabolite, are increased. Previously we reported that glyoxal-induced hepatocyte cytotoxicity could be attributed to mitochondrial toxicity as mitochondrial membrane potential was decreased and cytotoxicity was increased several orders of magnitude by low non-cytotoxic doses of H2O2 (hepatocyte inflammation model). In this study, we have assessed the toxicity of fructose towards hepatocytes and investigated the molecular cytotoxic mechanisms involved. Fructose itself was only toxic at 1.5 M, whereas 12 mM caused 50% cell death in 2 h if the hepatocytes were exposed to a non-cytotoxic dose of H2O2 continuously generated by glucose and glucose oxidase. The cytotoxic mechanism involved oxidative stress as ROS and H2O2 formation preceded cytotoxicity, and cytotoxicity was prevented by radical scavengers, lipid antioxidants and ROS scavengers. It is proposed that the highly potent Fenton derived ROS catalyse the oxidation of fructose and particularly its carbonyl metabolites glycolaldehyde, dihydroxyacetone, glyceraldehyde. The carbon radicals and glyoxal formed compromise the cell's resistance to H2O2. (C) 2008 Elsevier Ireland Ltd. All rights reserved.