A Metabonomics Study of the Hepatotoxicants Galactosamine, Methylene Dianiline and Clofibrate in Rats*

Ishihara, Kenji; Katsutani, Naruo; Aoki, Toyohiko

doi:10.1111/j.1742-7843.2006.pto_455.x

Cited by 22 publications

(22 citation statements)

References 40 publications

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“…A prominent finding was the depletion of the TCA cycle intermediates which were mainly located in liver mitochondria, including citrate, succinate, and 2-oxoglutarate, in urine samples from the combined group. These organic acids may be more universal markers for cellular liver pathology (Ishihara et al, 2006). The decreased levels of citrate, 2-oxoglutarate, and succinate in urine following PCBs and TCDD treatment could be a result of decreased fatty acid catabolism, since these metabolites are intermediates of the TCA cycle which occurs largely in liver mitochondria.…”

Section: Discussionmentioning

confidence: 99%

NMR-based metabonomic analysis of the hepatotoxicity induced by combined exposure to PCBs and TCDD in rats

Wang

Sheng

et al. 2010

Toxicology and Applied Pharmacology

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Section: Discussionmentioning

confidence: 99%

NMR-based metabonomic analysis of the hepatotoxicity induced by combined exposure to PCBs and TCDD in rats

Wang

Sheng

et al. 2010

Toxicology and Applied Pharmacology

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“…Metabolomic analysis has been introduced into toxicological research to obtain better understanding of the endogenous metabolic profile in several hepatic injury models over the last decade (Soga et al, 2006;Ishihara et al, 2006). One advantage of this evolving technology is to assess a number of endogenous metabolites in blood or urine at one time.…”

Section: Introductionmentioning

confidence: 99%

Metabolomic analysis of arginine metabolism in acute hepatic injury in rats

et al. 2014

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Blood alanine aminotransferase (ALT) has been widely used as a sensitive and specific biomarker of hepatotoxicity in preclinical and clinical settings. However, an increase in ALT has also been associated with skeletal muscle injury, indicating that the enzyme has specificity beyond liver injury in the absence of correlative histopathological changes in the liver (Nathwani et al., 2005). To reduce the risk of false positives derived from extraneous sources of ALT, additional biomarkers with improved specificity for hepatic injury compared to ALT alone are needed (Ozer et al., 2008).Blood arginine has been suggested as a biomarker candidate for hepatic injury because it was decreased in hepatic injuries induced by thioacetamide or carbon tetrachloride (Vijaya and Nagarajan, 1982, Trennery andWaring, 1983). Arginine is metabolized to ornithine and urea by arginase, an enzyme found primarily in the liver along with ALT (Jenkinson et al., 1996). Decreased blood arginine was well correlated with increased blood ornithine and arginase in several hepatic injury models (Vijaya and Nagarajan, 1982;Roth et al., 1994;Houdijk et al., 1997;Yagnik et al., 2002), indicating that increased blood arginase plays a crucial role in arginine metabolism. On the other hand, arginine is a versatile amino acid in animals, serving as a precursor not only for ornithine and urea but also for nitric oxide, citrulline, and creatine. Furthermore, blood arginine is affected by food intake, protein turnover, the supply of arginine via the kidney, and the catabolism (Wu and Morris, 1998 ABSTRACT -To clarify the relationship between arginine metabolism and hepatic injury, metabolomic analysis was performed in rats treated with 3 representative hepatotoxicants, monocrotaline (MCT), concanavalin A (ConA), and α-naphthyl isothiocyanate (ANIT); or a myotoxicant, tetramethyl-p-phenylenediamine (TMPD). A single dose of MCT, ConA, or ANIT dose-dependently induced hepatocellular necrosis accompanied by decreased blood arginine and increased blood alanine aminotransferase (ALT) and arginase. A close correlation was detected between arginine and ALT (r = -0.746, -0.795, -0.787 for MCT, ConA, ANIT, respectively) or between arginine and arginase (r = -0.605, -0.808, -0.672 for MCT, ConA, ANIT, respectively) in all three hepatic injury models. In contrast, neither hepatocellular necrosis nor alterations in arginine were found in the skeletal muscle injury model, although ALT was slightly increased. An in vitro assay revealed that blood samples obtained from ConA-treated rats transformed external arginine to ornithine, and the reaction was totally inhibited by an arginase inhibitor. These results suggest that blood arginase plays a crucial role in arginine metabolism associated with hepatic injury. In metabolomic analysis, nearly 450 endogenous metabolites were identified in blood obtained from all the models. Among the 13 metabolites involved in arginine metabolism, decreased arginine and increased ornithine occurred in common in the hepatic injury models, wh...

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“…To identify putative metabolites associated with cholestasis, urine samples obtained were subjected to 1 H nuclear magnetic resonance analysis. Previous studies using various types of hepatotoxicants (4,4¢-methylene dianiline, clofibrate and galactosamine) suggested that urinary metabolites with chemical shifts of 0.66 to 1.90 ppm were markedly affected by 4,4¢-methylene dianiline [12], which is known to induce cholestasis. The dose of 4,4¢-methylene dianiline, 250 mg/kg, oral administration, in one previous study was relatively high and might have injured tissues other than the liver [27].…”

Section: Discussionmentioning

confidence: 99%

“…peroxisome proliferation in the liver and hepatocyte death, respectively [12]. The most significant differences between the 4,4¢-methylene dianiline-treated groups (250 mg/kg oral administration) and groups treated with other agents (clofibrate 500 mg/kg oral administration, galactosamine 500 mg/kg intraperitoneal administration) were observed in chemical shifts of peaks mainly between 0.66 and 1.90 ppm.…”

mentioning

confidence: 92%

“…In a previous 1 H nuclear magnetic resonance metabonomics study, we investigated and compared the biochemical profiles of metabolites in urine from rats treated with hepatotoxicants with different mechanisms of effect [12]. We used 4,4¢-methylene dianiline as a model compound inducing bile duct injury, and clofibrate and galactosamine to produce models of Author for correspondence: Kenji Ishihara, Tsukuba Research, Drug Safety Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba 300-2635, Japan (fax + 81 29 847 6931, e-mail k3-ishihara@ hhc.eisai.co.jp).…”

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confidence: 99%

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

Ishihara

Katsutani

Asai

et al. 2009

Basic Clin Pharma Tox

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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.

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A Metabonomics Study of the Hepatotoxicants Galactosamine, Methylene Dianiline and Clofibrate in Rats*

Cited by 22 publications

References 40 publications

NMR-based metabonomic analysis of the hepatotoxicity induced by combined exposure to PCBs and TCDD in rats

NMR-based metabonomic analysis of the hepatotoxicity induced by combined exposure to PCBs and TCDD in rats

Metabolomic analysis of arginine metabolism in acute hepatic injury in rats

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

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