Discovery of common urinary biomarkers for hepatotoxicity induced by carbon tetrachloride, acetaminophen and methotrexate by mass spectrometry‐based metabolomics

Abstract

Liver toxicity represents an important healthcare issue because it causes significant morbidity and mortality and can be difficult to predict before symptoms appear owing to drug therapy or exposure to toxicants. Using metabolomic techniques, we discovered common biomarkers for the prediction of hepatotoxicity in rat urine using mass spectrometry. For this purpose, liver toxicity was induced by 5 days of oral administration of carbon tetrachloride (1 ml kg(-1) per day), acetaminophen (1000 mg kg(-1) per day) and methotrexate (50 mg kg(-1) per day). Serum levels of alkaline phosphatase aspartate aminotransferase, alanine aminotransferase and histopathology in liver tissue were then checked to demonstrate liver toxicity. Global metabolic profiling with UPLC-TOF-MS (ultraperformance liquid chromatography-mass spectrometry), multivariate analysis (partial least square-discriminant analysis, hierarchical analysis) and database searching were performed to discover common biomarkers for liver toxicity induced by these three compounds. Urinary concentrations of the newly discovered biomarkers were then quantified to confirm them as biomarkers of hepatotoxicity with targeted metabolic profiling using GC (gas chromatography)-MS and CE (capillary electrophoresis)-MS. In the results, steroids, amino acids and bile acids were metabolically changed between the control and drug-treated groups in global metabolic profiling; 11β-hydroxyandrosterone, epiandrosterone, estrone, 11-dehydrocorticosterone, glycine, alanine, valine, leucine, dl-ornithine, 3-methylhistidine, cholic acid and lithocholic acid were selected as liver toxicity biomarkers after performing targeted metabolic profiling. In conclusion, we discovered metabolite biomarkers belonging to three different metabolic pathways to check for liver toxicity with mass spectrometry from a metabolomics study that could be used to evaluate hepatotoxicity induced by drugs or other toxic compounds.

Ameliorative Effects of Hydroalcoholic Extract of Lavandula officinalis L. on Methotrexate-Induced Oxidative Stress in Rats

“…Results obtained from pervious study has been well supported our result that revealed elevation in liver enzymes level, who have demonstrated that MTX causes hepatotoxicity. [25][26][27] All these changes in the liver function tests in MTX -treated animals were considered the major evidences of the hepatoxicity of MTX. The present study showed oral administration of LOE significantly lowered the MTX induced serum levels ALT, AST and ALP as hepatic enzyme markers (Table1).…”

The Application of Omics Technologies to the Study of Mammalian Toxicology

“…Currently, the evaluation of renal function relies on the measurement of blood urea nitrogen and serum [145,146] creatinine, both of which exhibit relatively low sensitivity for the detection of renal damage. Therefore, it is important to identify new, sensitive and reliable renal toxicity biomarkers.…”

Evaluation of the indicative roles of seven potential biomarkers on hepato-nephrotoxicity induced by Genkwa Flos

“…Thus, the significantly changed endogenous metabolites were regarded as biomarkers for monitoring different diseases (Beger et al, 2010a). Recently, some metabonomics studies have been done to discover novel biomarkers for druginduced liver and kidney injuries (Boudonck et al, 2009;Kumar et al, 2012;Ma et al, 2010aMa et al, , 2010bWeiss and Kim 2011;Yang et al, 2012). According to the reported studies (Chan et al, 2008;Geenen et al, 2011;Kumar et al, 2012;Lenz et al, 2004;Uehara et al, 2014;Xu et al, 2011;Zhang et al, 2014;Zhao et al, 2012), several potential hepato-nephrotoxicity biomarkers come up, such as cholic acid (CA), taurine (TA), 5-oxoproline (5-OP), hippuric acid (HIP), uric acid (UA), 3-indoxyl sulfate (3-IS) and kynurenic acid (KA).…”