Targeted liquid chromatography-mass spectrometry analysis of serum acylcarnitines in acetaminophen toxicity in children

被引：48

作者：

Bhattacharyya, Sudeepa ^{[1
,2
]}

Yan, Ke ^{[3
]}

Pence, Lisa ^{[4
]}

Simpson, Pippa M. ^{[3
]}

Gill, Pritmohinder ^{[1
,2
]}

Letzig, Lynda G. ^{[1
,2
]}

Beger, Richard D. ^{[4
]}

Sullivan, Janice E. ^{[5
,6
,7
]}

Kearns, Gregory L. ^{[8
]}

Reed, Michael D. ^{[9
,10
]}

Marshall, James D. ^{[11
]}

Van Den Anker, John N. ^{[12
]}

James, Laura P. ^{[1
,2
,13
,14
]}

机构：

[1] Univ Arkansas Med Sci, Dept Pediat, Little Rock, AR 72202 USA

[2] Arkansas Childrens Hosp, Res Inst, Little Rock, AR 72202 USA

[3] Med Coll Wisconsin, Milwaukee, WI 53226 USA

[4] US FDA, Natl Ctr Toxicol Res, Div Syst Biol, Jefferson, AR 72079 USA

[5] Univ Louisville, Kosair Char Pediat Clin Res Unit, Dept Pediat, Louisville, KY 40202 USA

[6] Univ Louisville, Kosair Char Pediat Clin Res Unit, Dept Pharmacol & Toxicol, Louisville, KY 40202 USA

[7] Kosair Childrens Hosp, Louisville, KY 40202 USA

[8] Childrens Mercy Hosp, Div Pediat Pharmacol Med Toxicol & Therapeut Inno, Kansas City, MO 64108 USA

[9] Northeast Ohio Med Univ, Dept Pediat, Div Clin Pharmacol & Toxicol, Akron, OH 44038 USA

[10] Akron Childrens Hosp, Rebecca D Considine Res Inst, Akron, OH 44308 USA

[11] Childrens Hlth Care Syst, Ft Worth, TX 76104 USA

[12] Childrens Natl Med Ctr, Div Pediat Clin Pharmacol, Washington, DC 20010 USA

[13] Univ Arkansas Med Sci, Dept Pharmacol, Little Rock, AR 72205 USA

[14] Univ Arkansas Med Sci, Dept Toxicol, Little Rock, AR 72205 USA

来源：

BIOMARKERS IN MEDICINE | 2014年 / 8卷 / 02期

关键词：

-oxidation; acetaminophen; acylcarnitine; biomarker; clinical; hepatic; toxicity; INDUCED HEPATIC-NECROSIS; ACUTE LIVER-FAILURE; PROTEIN ADDUCTS; INDUCED HEPATOTOXICITY; CLOFIBRATE; METABOLOMICS; METABOLITES; MULTICENTER; MECHANISMS; OVERDOSE;

D O I：

10.2217/bmm.13.150

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Aim: 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. Materials & methods: 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. Results: 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. Conclusion: Perturbations in long-chain acylcarnitines in children with APAP toxicity suggest that mitochrondrial injury and associated impairment in the -oxidation of fatty acids are clinically relevant as biomarkers of APAP toxicity.

引用

页码：147 / 159

页数：13

共 32 条

[1] Acetaminophen-Induced Hepatotoxicity in Mice Occurs with Inhibition of Activity and Nitration of Mitochondrial Manganese Superoxide Dismutase [J].