Identification of Urinary Biomarkers Useful for Distinguishing a Difference in Mechanism of Toxicity in Rat Model of Cholestasis

Abstract

This 1 H nuclear magnetic resonance metabonomics study was aimed to determine urinary biomarkers of cholestasis resulting from inhibition of biliary secretion of bile or obstruction of bile flow. To inhibit biliary secretion of bile, cyclosporine A was administered to male Sprague-Dawley rats. Obstruction of bile flow was induced by administration of 4,4¢-methylene dianiline, a-naphthylisothiocyanate or bile duct ligation. Clinical pathological and histopathological examinations were performed to confirm cholestatic injury and 1 H nuclear magnetic resonance spectral data for urine samples were analysed to determine similarities and differences in profiles of metabolites using the Spotfire Ò . In cyclosporine A-treated groups, serum total bilirubin and bile acid were significantly increased but no remarkable hepatic histopathological-changes were observed. In 4,4¢-methylene dianiline-, a-naphthylisothiocyanate-and bile duct ligationtreated groups, serum alkaline phosphatase, c-glutamyltranspeptidase and total bilirubin levels increased significantly, and hepatic histopathological-changes were observed. On urinary 1 H nuclear magnetic resonance spectral analysis, area intensities derived from 0.66 to 1.90 ppm were decreased by cyclosporine A, whereas they were increased by other treatments. These metabolites were identified using the NMR suite Ò as bile acids, branched-chain amino acids, n-butyrate, propionate, methyl malonate and valerate. These metabolites were further investigated by K-means clustering analysis. The cluster of these metabolites is considered to be altered by cholestasis. We conclude that bile acids, valine and methyl malonate have a possibility to be urinary cholestatic biomarkers, which distinguish a difference in mechanism of toxicity.

Metabolomic and Lipidomic Biomarkers for Premalignant Liver Disease Diagnosis and Therapy

“…In the first such study, rat models of inhibited biliary secretion (intrahepatic) and obstructed bile flow (extrahepatic) were employed, and urine was analyzed by 1 H NMR. It was concluded that bile acids, valine, and methyl malonate were possible cholestatic biomarkers [77]. These biomarkers did not appear to be specific to cholestatic injury.…”

The metabolomic window into hepatobiliary disease

“…An NMR metabolomic study has been performed in rats in an attempt to use urinary biomarkers to distinguish the two mechanisms [98]. Metabolomics revealed that cholestasis induced in Fxr -null mice by a cholic acid diet resulted in increased urinary excretion of bile salt tetrols, predominantly 3α,6,7α,12α-tetrahydroxy-5β-cholestan-26-oyltaurine, due to an adaptive upregulation of the steroid-hydroxylating cytochrome P450 CYP3A11 in these mice [99].…”

Metabolomics-Based Screening of Biofilm-Inhibitory Compounds against Pseudomonas aeruginosa from Burdock Leaf

“…Dynamic changes of all small molecule metabolites of biological systems in response to external stimuli can be well analyzed in metabolomics [12,13,14]. Through investigating the changes of metabolome after the treating by drugs or plant components, multidimensional data of the whole research system can be obtained.…”