Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
Chem Biol Interact. 2011 May 30;191(1-3):315-21. doi: 10.1016/j.cbi.2011.02.027. Epub 2011 Mar 3.
Previously, we showed that dietary fructose or its carbonyl metabolites, glyceraldehyde and glycolaldehyde, could be oxidized by inflammatory reactive oxygen species (ROS), products of immune cells, to form highly toxic and genotoxic products, such as glyoxal. Glycolaldehyde-caused hepatocyte protein carbonylation likely resulted from glyoxal, an autoxidation product formed by ROS. Although hepatocyte protein carbonylation by glyoxal or d-glycolaldehyde was rapid, the product was unstable. Glyceraldehyde-induced protein carbonylation was slower and was also less cytotoxic. Non-toxic concentrations of H(2)O(2) were then used to mimic inflammation and oxidative stress associated with fructose-induced non-alcoholic steatohepatitis (NASH). A slow infusion of H(2)O(2) markedly increased glyoxal, glyceraldehyde, and glycolaldehyde-induced cytotoxicity and protein carbonylation. However, it had a smaller effect on glyceraldehyde-induced protein carbonylation. The cytotoxicities of both aldehydes were increased if glutathione (GSH)-depleted hepatocytes were used, presumably because of the increased ROS formation and subsequent glyoxal-induced protein carbonylation. Catalytic amounts of Cu or Fe increased the glycolaldehyde and glyceraldehyde-induced cytotoxicity and protein carbonylation resulting from autoxidation to glyoxal. Glyceraldehyde and glycolaldehyde were also detoxified by mitochondrial aldehyde dehydrogenase (ALDH2) as ALDH2 inhibitors increased their cytotoxicity. Hydroxypyruvate has not been previously tested for toxicity and was found to be the most toxic fructose metabolite. Catalytic amounts of Cu or Fe caused hydroxypruvate autoxidation, which formed extensive ROS, glycolaldehyde and glyoxal. Iron chelators EGTA or deferoxamine inhibited cytotoxicity as well as the extensive ROS formation. The Girard assay confirmed that glyoxal was a common autoxidation product from glyceraldehyde, glycolaldehyde and hydroxypyruvate.
先前，我们已经证明了饮食中的果糖或其羰基代谢物——甘油醛和乙二醇醛，可以被免疫细胞产生的炎症反应性氧物质（ROS）氧化，从而形成高度毒性和遗传毒性的产物，如乙二醛。ROS 形成的产物丙二醛可能导致了肝细胞蛋白羰基化，而丙二醛又是 ROS 自氧化形成的产物。虽然乙二醛或 D-甘油醛导致的肝细胞蛋白羰基化反应速度很快，但产物很不稳定。而甘油醛引起的蛋白羰基化反应速度较慢，细胞毒性也较小。接着，我们用非毒性浓度的 H₂O₂来模拟与果糖诱导的非酒精性脂肪性肝炎（NASH）相关的炎症和氧化应激。缓慢输注 H₂O₂可显著增加乙二醛、甘油醛和乙二醇醛诱导的细胞毒性和蛋白羰基化。然而，其对甘油醛诱导的蛋白羰基化的影响较小。当使用谷胱甘肽（GSH）耗竭的肝细胞时，两种醛的细胞毒性都会增加，这可能是因为 ROS 生成增加，随后导致乙二醛诱导的蛋白羰基化。催化量的 Cu 或 Fe 会增加乙二醛和甘油醛诱导的细胞毒性和蛋白羰基化，这是由于它们自氧化生成的乙二醛所致。线粒体醛脱氢酶（ALDH2）还可以将甘油醛和乙二醇醛解毒，因为 ALDH2 抑制剂会增加它们的细胞毒性。羟基丙酮酸以前没有进行过毒性测试，结果发现它是果糖毒性最大的代谢产物。催化量的 Cu 或 Fe 会导致羟基丙酮酸自氧化，从而形成大量的 ROS、甘油醛和乙二醛。铁螯合剂 EGTA 或去铁胺可以抑制细胞毒性以及广泛的 ROS 生成。Girard 测定证实，乙二醛是甘油醛、乙二醇醛和羟基丙酮酸的常见自氧化产物。
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