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Vitamin D3-induced hypercalcemia increases carbon tetrachloride-induced hepatotoxicity through elevated oxidative stress in mice.

ABSTRACT: The aim of this study was to determine whether calcium potentiates acute carbon tetrachloride (CCl4) -induced toxicity. Elevated calcium levels were induced in mice by pre-treatment with cholecalciferol (vitamin D3; V.D3), a compound that has previously been shown to induce hypercalcemia in human and animal models. As seen previously, mice injected with CCl4 exhibited increased plasma levels of alanine aminotransferase, aspartate aminotransferase, and creatinine; transient body weight loss; and increased lipid peroxidation along with decreased total antioxidant power, glutathione, ATP, and NADPH. Pre-treatment of these animals with V.D3 caused further elevation of the values of these liver functional markers without altering kidney functional markers; continued weight loss; a lower lethal threshold dose of CCl4; and enhanced effects on lipid peroxidation and total antioxidant power. In contrast, exposure to V.D3 alone had no effect on plasma markers of liver or kidney damage or on total antioxidant power or lipid peroxidation. The potentiating effect of V.D3 was positively correlated with elevation of hepatic calcium levels. Furthermore, direct injection of CaCl2 also enhanced CCl4-induced hepatic injury. Since CaCl2 induced hypercalcemia transiently (within 3 h of injection), our results suggest that calcium enhances the CCl4-induced hepatotoxicity at an early stage via potentiation of oxidative stress.

SUBMITTER: Yoshioka H

PROVIDER: S-EPMC5407844 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Vitamin D3-induced hypercalcemia increases carbon tetrachloride-induced hepatotoxicity through elevated oxidative stress in mice.

Yoshioka Hiroki H Usuda Haruki H Miura Nobuhiko N Fukuishi Nobuyuki N Nonogaki Tsunemasa T Onosaka Satomi S

PloS one 20170427 4

The aim of this study was to determine whether calcium potentiates acute carbon tetrachloride (CCl4) -induced toxicity. Elevated calcium levels were induced in mice by pre-treatment with cholecalciferol (vitamin D3; V.D3), a compound that has previously been shown to induce hypercalcemia in human and animal models. As seen previously, mice injected with CCl4 exhibited increased plasma levels of alanine aminotransferase, aspartate aminotransferase, and creatinine; transient body weight loss; and ...[more]

PMID: 28448545

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Project description:BackgroundHydrogen sulfide (H(2)S) displays vasodilative, anti-oxidative, anti-inflammatory and cytoprotective activities. Impaired production of H(2)S contributes to the increased intrahepatic resistance in cirrhotic livers. The study aimed to investigate the roles of H(2)S in carbon tetrachloride (CCl(4))-induced hepatotoxicity, cirrhosis and portal hypertension.Methods and findingsSodium hydrosulfide (NaHS), a donor of H(2)S, and DL-propargylglycine (PAG), an irreversible inhibitor of cystathionine ?-lyase (CSE), were applied to the rats to investigate the effects of H(2)S on CCl(4)-induced acute hepatotoxicity, cirrhosis and portal hypertension by measuring serum levels of H(2)S, hepatic H(2)S producing activity and CSE expression, liver function, activity of cytochrome P450 (CYP) 2E1, oxidative and inflammatory parameters, liver fibrosis and portal pressure. CCl(4) significantly reduced serum levels of H(2)S, hepatic H(2)S production and CSE expression. NaHS attenuated CCl(4)-induced acute hepatotoxicity by supplementing exogenous H(2)S, which displayed anti-oxidative activities and inhibited the CYP2E1 activity. NaHS protected liver function, attenuated liver fibrosis, inhibited inflammation, and reduced the portal pressure, evidenced by the alterations of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), hyaluronic acid (HA), albumin, tumor necrosis factor (TNF)-?, interleukin (IL)-1?, IL-6 and soluble intercellular adhesion molecule (ICAM)-1, liver histology, hepatic hydroxyproline content and ?-smooth muscle actin (SMA) expression. PAG showed opposing effects to NaHS on most of the above parameters.ConclusionsExogenous H(2)S attenuates CCl(4)-induced hepatotoxicity, liver cirrhosis and portal hypertension by its multiple functions including anti-oxidation, anti-inflammation, cytoprotection and anti-fibrosis, indicating that targeting H(2)S may present a promising approach, particularly for its prophylactic effects, against liver cirrhosis and portal hypertension.

Project description:The aim of the presented work involves the isolation, characterization, and evaluation of hepatoprotective potential of Clerodendrum paniculatum flower extracts. For this purpose, petroleum ether, chloroform, ethyl acetate, alcohol, and water extracts of C. paniculatum flower were screened for the flavonoid and phenolic content and quantified. Various antioxidant activity assays including 2,2'-diphenyl-1-picrylhydrazyl (DPPH), nitric oxide (NO) radical scavenging, 2,2-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), and reducing ability were carried out. Of the above methods, the alcoholic extract exhibited high antioxidant potential and was selected further for the hepatoprotective evaluations. Hepatoprotective evaluation of the alcoholic extract was carried out for carbon tetrachloride (CCl4)-intoxicated model systems. Enzymes associated with liver functions were estimated, and histopathological evaluations were carried out to monitor the liver architecture. Prominently, reduced levels of various associated enzymes along with increased protein content were observed when the liver specimen was pretreated with the extract. Moreover, the liver architecture was almost comparable to that of the normal control group. The column chromatographic analysis of the extract revealed 13 fractions to possess high phenolics and flavonoid contents. The best two fractions were identified for in vitro hepatoprotective evaluation in the goat liver model. Furthermore, the GC-MS analyses of the fractions were carried out followed by a library search, to identify the constituents responsible for the hepatoprotective activity which revealed the presence of four major constituents-pilocarpine, glyceric acid, pangamic acid, and gallic acid. An in vitro hepatoprotective study of the isolated fractions showed better activity compared to the whole alcoholic extract, and the results were comparable to the normal group taken as a control. The investigations with an in vitro model suggest that the isolated fraction with rich flavonoid content showed better hepatoprotective activity. GC-MS analysis of the fractions that displayed good hepatoprotective activity suggested the presence of pilocarpine, glyceric acid, pangamic acid, and gallic acid, while HPTLC analysis revealed the presence of quercetin.

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Dataset Information

Vitamin D3-induced hypercalcemia increases carbon tetrachloride-induced hepatotoxicity through elevated oxidative stress in mice.

Publications

Vitamin D3-induced hypercalcemia increases carbon tetrachloride-induced hepatotoxicity through elevated oxidative stress in mice.

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