Targeted liquid chromatography-mass spectrometry analysis of serum acylcarnitines in acetaminophen toxicity in children.
Targeted liquid chromatography-mass spectrometry analysis of serum acylcarnitines in acetaminophen toxicity in children.
复制标题
DOI：
10.2217/bmm.13.150
复制
发表时间：
2014
影响因子：
2.2
通讯作者：
James LP
中科院分区：
文献类型：
--
作者：
Bhattacharyya S;Yan K;Pence L;Simpson PM;Gill P;Letzig LG;Beger RD;Sullivan JE;Kearns GL;Reed MD;Marshall JD;Van Den Anker JN;James LP
在对乙酰氨基酚(APAP)诱导的小鼠肝损伤模型中，长链酰基肉碱被认为是敏感的生物标志物。在接下来的研究中，研究了接受低剂量(治疗性)和高剂量(过量或有毒摄入)APAP暴露的儿童的酰基肉碱与其他已知的APAP毒性指标的关系。研究包括三组受试者：A组(治疗剂量，n=187)；B组(健康对照组，n=23)；C组(过量剂量，n=62)。收集了每个受试者的人口统计学、临床和实验室数据。血清标本用于APAP氧化代谢的生物标志物APAP蛋白加合物的测定，并用超高效液相色谱-三重四极杆质谱仪进行血清酰基肉碱的靶向代谢组学分析。与对照组相比，APAP暴露(低剂量和过量)时，油酰肉碱和棕榈酰肉碱显著增加。在接受解毒剂N-乙酰半胱氨酸延迟治疗(从过量到治疗24小时)的过量儿童中，观察到血清丙氨酸氨基转移酶、APAP蛋白加合物和酰肉碱显著增加。血清APAP蛋白加合物达峰时间明显短于酰肉碱和血清ALT。APAP中毒儿童的长链酰卡尼汀的扰动提示，线粒体损伤和相关的脂肪酸β氧化损伤是APAP中毒的临床相关生物标志物。
Long-chain acylcarnitines have been postulated to be sensitive biomarkers of acetaminophen (APAP)-induced hepatotoxicity in mouse models. In the following study, the relationship of acylcarnitines with other known indicators of APAP toxicity was examined in children receiving low-dose (therapeutic) and high-dose (‘overdose’ or toxic ingestion) exposure to APAP. The study included three subject groups: group A (therapeutic dose, n = 187); group B (healthy controls, n = 23); and group C (overdose, n = 62). Demographic, clinical and laboratory data were collected for each subject. Serum samples were used for measurement of APAP protein adducts, a biomarker of the oxidative metabolism of APAP and for targeted metabolomics analysis of serum acylcarnitines using ultra performance liquid chromatography–triple-quadrupole mass spectrometry. Significant increases in oleoyl- and palmitoyl-carnitines were observed with APAP exposure (low dose and overdose) compared with controls. Significant increases in serum ALT, APAP protein adducts and acylcarnitines were observed in overdose children that received delayed treatment (time to treatment from overdose >24 h) with the antidote N-acetylcysteine. Time to peak APAP protein adducts in serum was shorter than that of the acylcarnitines and serum ALT. Perturbations in long-chain acylcarnitines in children with APAP toxicity suggest that mitochrondrial injury and associated impairment in the β-oxidation of fatty acids are clinically relevant as biomarkers of APAP toxicity.