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首页> 外文期刊>Archives of Toxicology >Circulating acylcarnitines as biomarkers of mitochondrial dysfunction after acetaminophen overdose in mice and humans
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Circulating acylcarnitines as biomarkers of mitochondrial dysfunction after acetaminophen overdose in mice and humans

机译：对乙酰氨基酚过量后小鼠和人类中循环酰基肉碱作为线粒体功能障碍的生物标志物

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Acetaminophen (APAP) is a widely used analgesic. However, APAP overdose is hepatotoxic and is the primary cause of acute liver failure in the developed world. The mechanism of APAP-induced liver injury begins with protein binding and involves mitochondrial dysfunction and oxidative stress. Recent efforts to discover blood biomarkers of mitochondrial damage have identified increased plasma glutamate dehydrogenase activity and mitochondrial DNA concentration in APAP overdose patients. However, a problem with these markers is that they are too large to be released from cells without cell death or loss of membrane integrity. Metabolomic studies are more likely to reveal biomarkers that are useful at early time points, before injury begins. Similar to earlier work, our metabolomic studies revealed that acylcarnitines are elevated in serum from mice after treatment with toxic doses of APAP. Importantly, a comparison with furosemide demonstrated that increased serum acylcarnitines are specific for mitochondrial dysfunction. However, when we measured these compounds in plasma from humans with liver injury after APAP overdose, we could not detect any significant differences from control groups. Further experiments with mice showed that N-acetylcysteine, the antidote for APAP overdose in humans, can reduce acylcarnitine levels in serum. Altogether, our data do not support the clinical measurement of acylcarnitines in blood after APAP overdose due to the standard N-acetylcysteine treatment in patients, but strongly suggest that acylcarnitines would be useful mechanistic biomarkers in other forms of liver injury involving mitochondrial dysfunction.
机译：对乙酰氨基酚（APAP）是一种广泛使用的止痛药。但是，过量服用APAP具有肝毒性，是发达国家急性肝衰竭的主要原因。 APAP诱导的肝损伤的机制始于蛋白质结合，并涉及线粒体功能障碍和氧化应激。在发现过量APAP的患者中，发现线粒体损伤的血液生物标志物的最新努力已发现血浆谷氨酸脱氢酶活性和线粒体DNA浓度增加。但是，这些标记的问题在于它们太大而不能从细胞中释放出来而不会导致细胞死亡或膜完整性丧失。代谢组学研究更有可能揭示在损伤开始之前的早期时间点有用的生物标志物。与早期的工作相似，我们的代谢组学研究表明，用有毒剂量的APAP处理后，小鼠血清中的酰基肉碱含量升高。重要的是，与呋塞米的比较表明，血清酰基肉碱的增加对线粒体功能障碍具有特异性。但是，当我们在过量使用APAP后从患有肝损伤的人的血浆中测量这些化合物时，我们无法检测到与对照组的任何显着差异。小鼠的进一步实验表明，人APAP过量的解毒剂N-乙酰半胱氨酸可以降低血清中的酰基肉碱水平。总之，由于标准的N-乙酰半胱氨酸治疗，APAP用药过量后血液中酰基肉碱的临床测量不支持临床研究，但强烈建议酰基肉碱在其他形式的涉及线粒体功能障碍的肝损伤中将是有用的生物标志物。

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