Perturbation of bile acid homeostasis is an early pathogenesis event of drug induced liver injury in rats

Yamazaki, Makoto; Miyake, Manami; Sato, Hiroko; Masutomi, Naoya; Tsutsui, Naohisa; Adam, Klaus-Peter; Alexander, Danny; Lawton, Kay A.; Milburn, Michael V.; Ryals, John; Wulff, Jacob; Guo, Lining

doi:10.1016/j.taap.2013.01.018

Cited by 99 publications

(86 citation statements)

References 39 publications

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“…Hydrazine challenge caused a significant increase in lipid peroxidation (measured as increases in MDA contents) in hepatic tissue of the rats, as previously observed 5,28,29 , to 1.27 ± 0.08 nmol/mg protein, indicating hydrazine intoxication (Fig. 9).…”

Section: Effect Of Maks On Mda Contentssupporting

confidence: 84%

“…A number of drugs, chemicals, and viruses re-portedly cause severe liver necrosis, which can be difficult to treat 3,4,21,25,27,28 . Thus it is highly important to identify compounds that could ameliorate liver damage and hepatic failure.…”

Section: Discussionmentioning

confidence: 99%

“…Partly because several kinds of free radicals are produced in the liver during their elimination, various deleterious agents can induce inflammation, fibrosis, necrosis, and eventually cirrhosis and functional deterioration of the organ 28 . Acute and chronic liver diseases are of global concerns, and medical treatments often involve difficult protocols and have limited efficiency 29 .…”

Section: Introductionmentioning

confidence: 99%

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Characterization of melanin extracted from apricot (Armeniaca sibirica) and its effect on hydrazine-induced rat hepatic injury

Li¹,

Li²,

Zhao³

2016

ScienceAsia

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ABSTRACT:Melanin is a complex, highly coloured natural antioxidant with potent biological activities and diverse applications. A potential source of melanin is the Siberian apricot (Armeniaca sibirica) whose kernel skin is currently a waste by-product. To explore its potential, melanin from apricot kernel skin was extracted. The molecular mass was determined by gel chromatography and its structure was examined by elemental analysis, UV-Vis, infrared, and solid-state nuclear magnetic resonance ( 13 C-NMR) spectroscopy. In addition, its protective effect against hydrazineinduced hepatic injury in rats was evaluated. The results showed that melanin has < 5% sulphur (S) content, indicating that it consists mostly of eumelanin. Its UV-Vis, infrared and 13 C-NMR spectra were very similar to those of synthetic melanin, although it had relatively high carboxylate, aliphatic, and phenol-skeleton content. Two distinct fractions (2.4 ± 0.12 and 0. ± 560.1 kDa) were detected. Injections of hydrazine at 65 mg/kg body-weight (b.wt.) doses resulted in significant (p < 0.01) increases in lipid peroxidation (malondialdehyde contents) in liver homogenates and serum alanine aminotransferase and aspartate aminotransferase activities (64%, 69%, and 98% increase relative to the controls, respectively). It also induced significant (p < 0.05 or 0.01) decreases in liver homogenate catalase, glutathione peroxidase, and superoxide dismutase activities and reduced glutathione content (48%, 28%, 7%, and 98% reduction, respectively). Administering melanin prior to hydrazine, at 10 mg/kg b.wt., strongly inhibited these changes and ameliorated histopathological hepatic injury. The results indicated that melanin alleviated hydrazine-induced liver injury by relieving oxidative stress, which may provide a novel protective strategy for protection against liver diseases.

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Section: Effect Of Maks On Mda Contentssupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Characterization of melanin extracted from apricot (Armeniaca sibirica) and its effect on hydrazine-induced rat hepatic injury

Li¹,

Li²,

Zhao³

2016

ScienceAsia

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“…Cholestasis results in a dramatic increase in liver and serum bile acid levels that eventually leads to acute liver toxicity, proliferation of bile ducts, and fibrosis that progresses to cirrhosis [1] . Cholestasis is often divided into two categories (intrahepatic or extrahepatic) based on its etiology.…”

Section: Introductionmentioning

confidence: 99%

Resveratrol effectively attenuates α-naphthyl-isothiocyanate-induced acute cholestasis and liver injury through choleretic and anti-inflammatory mechanisms

et al. 2014

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Aim: α-Naphthylisothiocyanate (ANIT) is a well-characterized cholestatic agent for rats. The aim of this study was to examine whether resveratrol could attenuate ANIT-induced acute cholestasis and liver injury in rats. Methods: SD rats were treated with resveratrol (15 or 30 mg/kg, ip) or a positive control drug ursodeoxycholic acid (100 mg/kg, po) for 5 consecutive days followed by a single dose of ANIT (60 mg/kg, po). Bile flow, and serum biochemical markers and bile constituents were measured 48 h after ANIT administration. Hepatic levels of oxidative repair enzymes (glutathione peroxidase, catalase and MnSOD), myeloperoxidase activity, TNF-α, IL-6, and ATP content, as well as the expression of liver transporter genes and proteins were assayed. Results: ANIT exposure resulted in serious cholestasis and liver injury, as shown by marked neutrophil infiltration in liver, dramatically increased serum levels of ALT, AST, GGT, ALP, TBA, TBIL, IBIL, and DBIL, and significantly decreased bile excretion and biliary output of GSH and HCO 3 -. ANIT significantly increased TNF-α and IL-6 release and myeloperoxidase activity, decreased mitochondrial biogenesis in liver, but had little effect on hepatic oxidative repair enzymes and ATP content. Furthermore, ANIT significantly decreased the expression of Mrp2, FXR, and Cyp7a1, markedly increased Mrp3 expression in liver. Pretreatment with resveratrol attenuated ANITinduced acute cholestasis and liver injury, and other pathological changes. Pretreatment with ursodeoxycholic acid was less effective. Conclusion: Resveratrol effectively attenuates ANIT-induced acute cholestasis and liver injury in rats, possibly through suppression of neutrophil infiltration, as well as upregulation of expression of hepatic transporters and enzymes, thus decreasing accumulation of bile acids.

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“…In an attempt to identify potential biomarkers for improved DILI detection by untargeted metabolomics, significant elevations of a panel of BAs in plasma and urine of rats treated with different types of hepatotoxins were found [93]. Other groups reported changes in metabolites derived from energy [94,95], urea and BA metabolism in urine and blood of mice or rats treated with a single dose of acetaminophen (APAP), which strongly correlated with the development of hepatic necrosis [96].…”

Section: Bile Acids As Surrogate Markersmentioning

confidence: 99%

Bile acids in drug induced liver injury: Key players and surrogate markers

Schadt

Wolf

Philippe

et al. 2016

Clinics and Research in Hepatology and Gastroenterology

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Bile acid research has gained great momentum since the role of bile acids as key signaling molecules in the enterohepatic circulation was discovered. Their physiological function in regulating their own homeostasis, as well as energy and lipid metabolism make them interesting targets for the pharmaceutical industry in the context of diseases such as bile acid induced diarrhea, bile acid induced cholestasis or nonalcoholic steatohepatitis. Changes in bile acid homeostasis are also linked to various types of drug-induced liver injury (DILI). However, the key question whether bile acids are surrogate markers for monitoring DILI or key pathogenic players in the onset and progression of DILI is under intense investigation. The purpose of this review is to summarize the different facets of bile acids in the context of normal physiology, hereditary defects of bile acid transport and DILI.

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Perturbation of bile acid homeostasis is an early pathogenesis event of drug induced liver injury in rats

Cited by 99 publications

References 39 publications

Characterization of melanin extracted from apricot (Armeniaca sibirica) and its effect on hydrazine-induced rat hepatic injury

Characterization of melanin extracted from apricot (Armeniaca sibirica) and its effect on hydrazine-induced rat hepatic injury

Resveratrol effectively attenuates α-naphthyl-isothiocyanate-induced acute cholestasis and liver injury through choleretic and anti-inflammatory mechanisms

Bile acids in drug induced liver injury: Key players and surrogate markers

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