Boots Agnes W, Li Hui, Schins Roel P F, Duffin Rodger, Heemskerk Johan W M, Bast Aalt, Haenen Guido R M M
Department of Pharmacology and Toxicology, Faculty of Medicine, University of Maastricht, PO Box 616, 6200 MD Maastricht, The Netherlands.
Toxicol Appl Pharmacol. 2007 Jul 1;222(1):89-96. doi: 10.1016/j.taap.2007.04.004. Epub 2007 Apr 24.
Free radical scavenging antioxidants, such as quercetin, are chemically converted into oxidation products when they protect against free radicals. The main oxidation product of quercetin, however, displays a high reactivity towards thiols, which can lead to the loss of protein function. The quercetin paradox is that in the process of offering protection, quercetin is converted into a potential toxic product. In the present study, this paradox is evaluated using rat lung epithelial (RLE) cells. It was found that quercetin efficiently protects against H(2)O(2)-induced DNA damage in RLE cells, but this damage is swapped for a reduction in GSH level, an increase in LDH leakage as well as an increase of the cytosolic free calcium concentration. To our knowledge, this is the first study that indicates that the quercetin paradox, i.e. the exchange of damage caused by quercetin and its metabolites, also occurs in living lung cells. Following depletion of GSH in the cells by BSO pre-treatment, this quercetin paradox becomes more pronounced, confirming that the formation of thiol reactive quercetin metabolites is involved in the quercetin paradox. The quercetin paradox in living cells implies that the anti-oxidant directs oxidative damage selectively to thiol arylation. Apparently, the potential toxicity of metabolites formed during the actual antioxidant activity of free radical scavengers should be considered in antioxidant supplementation.
自由基清除抗氧化剂，如槲皮素，在抵御自由基时会发生化学转化生成氧化产物。然而，槲皮素的主要氧化产物对硫醇具有高反应性，这可能导致蛋白质功能丧失。槲皮素悖论在于，在提供保护的过程中，槲皮素会转化为一种潜在的有毒产物。在本研究中，利用大鼠肺上皮（RLE）细胞对这一悖论进行了评估。研究发现，槲皮素能有效保护RLE细胞免受H₂O₂诱导的DNA损伤，但这种保护是以谷胱甘肽（GSH）水平降低、乳酸脱氢酶（LDH）泄漏增加以及胞质游离钙浓度升高为代价的。据我们所知，这是第一项表明槲皮素悖论（即槲皮素及其代谢产物所造成的损伤交换）也发生在活的肺细胞中的研究。在用丁硫氨酸亚砜胺（BSO）预处理使细胞内GSH耗竭后，这种槲皮素悖论变得更加明显，证实了硫醇反应性槲皮素代谢产物的形成与槲皮素悖论有关。活细胞中的槲皮素悖论意味着抗氧化剂将氧化损伤选择性地导向硫醇芳基化。显然，在补充抗氧化剂时应考虑自由基清除剂实际抗氧化活性过程中形成的代谢产物的潜在毒性。
