Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A variety of hepatobiliary abnormalities occur in inflammatory bowel diseases (IBDs). The role of tight junction (TJ) in hepatobiliary complications have been well described. The purpose of this study was to investigate the role of inducible nitric oxide (NOS) in alteration of hepatocyte TJ paracellular barrier and in the rapid transcytotic vesicular pathway modification associated with intestinal inflammation. To address this question, we used an experimental model of colitis, induced by dinitrobenzene sulfonic acid (DNBS). When compared to DNBS-treated iNOS wild-type (WT) mice, DNBS-treated iNOS knock out mice (iNOSKO) mice experienced a significant less rate of the extent and severity of the histological signs of colon injury. Colon levels of the pro-inflammatory cytokines tumour necrosis factor, interleukin-1beta and interleukin-6 were also significantly reduced in iNOS-KO mice in comparison to wild-type mice. Liver histology from iNOSKO and wild-type mice iNOSWT did not show any parenchymal and portal tract inflammation at 4 days after DNBS administration. Serum total bilirubin and alanine aminotransferase, were significantly reduced in DNBS-iNOSKO mice vs DNBS-iNOSKO mice. Therefore, we found an increase of tight junctional permeability to lanthanum nitrate (molecular weight, 433) in the livers from DNBS-treated IL-10WT mice, lanthanum accumulated throughout the junctional area up to the most apical region bordering the lumen. Absence of a functional iNOS gene in iNOSKO mice resulted in a significant reduction of apical diffusion of lanthanum after DNBS-induced colitis. Immunofluorescent labeling of frozen liver sections from DNBS-iNOSWT mice showed a significant alteration of the immunolocalization for claudin-1 and zonula occludens (ZO)-1. In contrast, a significant reduced alteration in the localization of the immunosignals for claudin-1 and ZO-1 was observed in the liver from iNOSKO mice after DNBS administration. In conclusion, we suggest that the iNOS may represent an important pathophysiological mechanism of hepatobiliary injuries and cholestasis observed in patients with IBD.
Cell Mol Biol (Noisy-le-grand) 2003 Feb
PMID:Role of iNOS in hepatocyte tight junction alteration in mouse model of experimental colitis. 1283 36

Retinol binding protein (RBP) in plasma of rats treated with carbon tetrachloride (CCl4) was monitored to clarify if RBP is available for the evaluation of the drug-induced hepatotoxicity. Blood was withdrawn by heart puncture at 0 hr and 12 hr after i.p. administration of CCl4 (0.2 ml/kg) to rats. Lactate dehydrogenase (LDH) and alanine aminotransferase (ALT) in plasma significantly increased at 12 hr after CCl4 administration, compared with the control, while RBP in plasma significantly decreased. On the other hand, albumin in plasma was unaffected at 12 hr after CCl4 administration. Thus RBP seems to monitor the different aspects in the drug-induced hepatotoxicity from LDH and ALT, and from the viewpoint of protein synthesis in the liver, to be more sensitively affected by the drug-induced hepatotoxicity than albumin.
Res Commun Mol Pathol Pharmacol 2001
PMID:Retinol binding protein in plasma to evaluate the hepatotoxicity of rats treated with CCl4. 1288 22

Cytosolic alanine aminotransferase (c-AAT) was purified up to 203- and 120-fold, from the liver of two freshwater teleosts Clarias batrachus (air-breathing, carnivorous) and Labeo rohita (water-breathing, herbivorous), respectively. The enzyme from both fish showed similar elution profiles on a DEAE-Sephacel ion exchange column. SDS-PAGE of purified enzymes revealed two subunits of 54 and 56 kDa, in both fish. The apparent Km values for l-alanine were 18.5+/-0.48 and 23.55+/-0.60 mM, whereas for 2-oxoglutarate the Km values were observed to be 0.29+/-0.023 and 0.33+/-0.028 mM for the enzyme from C. batrachus and L. rohita, respectively. With l-alanine as substrate, aminooxyacetic acid was found to act as a competitive inhibitor with KI values of 6.4 x 10(-4) and 3.4 x 10(-4) mM with c-AAT of C. batrachus and L. rohita, respectively. However, when 2-oxoglutarate was used as substrate, aminooxyacetic acid showed uncompetitive inhibition with similar KI values for purified c-AAT from both fish. Temperature and pH profiles of the enzyme did not show any marked differences between the two fish examined. These results suggest that liver c-AAT, isolated from these two fish species adapted to different modes of life, remain unaltered structurally. However, at the kinetic level, liver c-AAT from C. batrachus exhibits significantly higher affinity for the substrate l-alanine and decreased affinity for its metabolic inhibitor, in comparison to that of the enzyme purified from L. rohita. Such functional changes seem to be of physiological significance and also provide preliminary evidence for subtle changes in the enzyme as a mark of metabolic adaptation in the fish to different physiological demands.
Comp Biochem Physiol B Biochem Mol Biol 2004 Feb
PMID:Purification and properties of cytosolic alanine aminotransferase from the liver of two freshwater fish, Clarias batrachus and Labeo rohita. 1499 Feb 16

DT388GMCSF, a fusion toxin composed of the NH2-terminal region of diphtheria toxin (DT) fused to human granulocyte-macrophage colony-stimulating factor (GMCSF) has shown efficacy in the treatment of acute myeloid leukemia. However, the primary dose-limiting side effect is liver toxicity. We have reproduced liver toxicity in rats using the rodent cell-tropic DT-murine GMCSF (DT390mGMCSF). Serum aspartate aminotransferase and alanine aminotransferase were elevated 15- and 4-fold, respectively, in DT390mGMCSF-treated rats relative to controls. Histologic analysis revealed hepatocyte swelling; however, this did not lead to hepatic necrosis or overt histopathologic changes in the liver. Immunohistochemical staining showed apoptotic cells in the sinusoids, and depletion of cells expressing the monocyte/macrophage markers, ED1 and ED2, indicating that Kupffer cells (KC) are targets of DT390mGMCSF. In contrast, sinusoidal endothelial cells seemed intact. In vitro, DT390mGMCSF was directly cytotoxic to primary KC but not hepatocytes. Two related fusion toxins, DT388GMCSF, which targets the human GMCSF receptor, and DT390mIL-3, which targets the rodent IL-3 receptor, induced a less than 2-fold elevation in serum transaminases and did not deplete KC in vivo. In addition, DTU2mGMCSF, a modified form of DT390mGMCSF with enhanced tumor cell specificity, was not hepatotoxic and was significantly less toxic to KC in vivo and in vitro. These results show that DT390mGMCSF causes liver toxicity by targeting KC, and establish a model for studying how this leads to hepatocyte injury. Furthermore, alternative fusion toxins with potentially reduced hepatotoxicity are presented.
Mol Cancer Ther 2004 Dec
PMID:Diphtheria toxin-murine granulocyte-macrophage colony-stimulating factor-induced hepatotoxicity is mediated by Kupffer cells. 1563 63

The oxidative stress induced by chronic ethanol consumption, particularly in concert with the aging process, has been implicated in changes in the structure and functions of liver cell components including membrane phospholipids. To counteract such changes, particularly those resulting from lipid peroxidation, antioxidants may be applied. Green tea contains large amounts of polyphenols, mainly catechins, which possess antioxidant properties. The aim of this study was to estimate the efficacy of green tea's influence on the physicochemical and biochemical properties of the rat liver as affected by the aging process and/or chronic ethanol intoxication. Several methods were used to evaluate this effect. Antioxidant properties were evaluated by vitamin E and antioxidant status determination. The liver trigliceride and cholesterol levels were also estimated. The extent of lipid peroxidation was determined by measuring the level of lipid peroxidation products as thiobarbituric reactive substances (TBARS). The surface charge density of the rat liver cells was measured using electrophoresis. The concentration of the marker enzymes of liver damage (alanine aminotransferase and aspartate aminotransferase) in the blood serum was also evaluated. Relative to the controls, aging was found to cause a decrease in the liver's antioxidant abilities and provoke an increase in the level of lipid peroxidation; it also increased the surface charge density of the rat liver cell membrane. Ethanol significantly aggravated these changes. This might have resulted in the liver cell membrane damage visible as a leak of alanine aminotransferase and aspartate aminotransferase into the blood. The ingestion of green tea with ethanol partially prevented these aging and/or ethanol-induced changes. Long-term drinking of green tea partially prevents the changes in the structure and function of the cell membrane caused by chronic ethanol intoxication.
Cell Mol Biol Lett 2004
PMID:Green tea modulation of the biochemical and electric properties of rat liver cells that were affected by ethanol and aging. 1564 93

We have previously shown that fructose-1,6-diphosphate (FDP) stimulates the synthesis of nitric oxide probably by stimulating the hepatic inducible nitric oxide synthase (iNOS). The aim of the present study was to evaluate the hepatoprotective role of FDP in acetaminophen-induced liver injury and whether this hepatoprotective effect is mediated by nitric oxide. Liver injury was induced in adult Sprague-Dawley rats by the administration of acetaminophen (1.6 g/kg by gavage) 10 min prior to the intraperitoneal injection of either FDP or normal saline. Liver injury was assessed by alanine aminotransferase (ALT) activity in the serum. iNOS and malondialdehyde (MDA) levels were determined in liver homogenates. Acetaminophen produced striking elevations of serum ALT, high MDA levels and a profound decrease in the liver iNOS. Administration of FDP attenuated the ALT and MDA elevations and prevented the liver iNOS depletion caused by acetaminophen. Pretreatment of the animals with the iNOS inhibitor L-NAME abolished this hepatoprotection. These findings suggest that FDP protects against acetaminophen-induced liver injury, at least partly, by stimulating production of nitric oxide.
Res Commun Mol Pathol Pharmacol 2003
PMID:Fructose diphosphate attenuates the acetaminophen-induced liver injury in the rat evidence for involvement of nitric oxide. 1568 24

Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) results in a broad spectrum of toxic effects. Most, if not all, of these responses are dependent upon the binding of dioxin to the aryl hydrocarbon receptor. Given their common roles in chemically induced toxicity, we asked whether interleukin 1 (IL1)-like cytokines play a role in acute aspects of the dioxin response. To test this idea, we employed a "triple-null" mouse model that lacks the two receptors for the tumor necrosis factors-alpha and -beta and the receptor for the IL1-alpha and IL1-beta cytokines. When triple null mice were treated with dioxin, there was significant attenuation in the levels of serum alanine aminotransferase, signifying reduced hepatocellular damage. In addition, the triple-null mice were protected from dioxin-induced liver inflammation. Loss of receptors for the IL1-like cytokines was not protective for all aspects of dioxin toxicity. Endpoints such as thymic involution, Cyp1a2 induction, hepatomegaly, and hydropic degeneration remain unchanged in this model.
Mol Pharmacol 2005 May
PMID:Aspects of dioxin toxicity are mediated by interleukin 1-like cytokines. 1572 56

Obesity is not necessary to observe insulin resistance in humans since severe insulin resistance also characterizes patients lacking subcutaneous fat such as those with HAART (highly-active antiretroviral therapy) - associated lipodystrophy. Both the obese and the lipodystrophic patients have, however, an increase in the amount of fat hidden in the liver. Liver fat content can be non-invasively accurately quantified by proton magnetic resonance spectroscopy. It is closely correlated with fasting insulin and direct measures of hepatic insulin sensitivity while the amount of subcutaneous adipose tissue is not. The causes of interindividual variation in liver fat content independent of obesity are largely unknown but could involve differences in signals from adipose tissue such as in the amount of adiponectin produced and differences in fat intake. Adiponectin deficiency characterizes both lipodystrophic and obese insulin resistant individuals, and serum levels correlate with liver fat content. Liver fat content can be decreased by weight loss. In addition, treatment of both lipodystrophic and type 2 diabetic patients with PPARgamma agonists but not metformin decreases liver fat and increases adiponectin levels. Markers of liver fat such as serum alanine aminotransferase activity have been shown to predict type 2 diabetes in several studies independent of obesity. The fatty liver thus may help to explain why some but not all obese individuals are insulin resistant and why even lean individuals may be insulin resistant, and thereby at risk of developing type 2 diabetes and cardiovascular disease.
Curr Mol Med 2005 May
PMID:The fatty liver and insulin resistance. 1589 48

Fertile chicken eggs were injected with various concentrations of either d-glucose or l-glucose during the first three days of embryonic development. The exogenous glucose concentrations ranged from 0 to 18.58 micromol/kg egg. At 18 days of development (theoretical stage 44), brains, livers, and blood from chorio-allantoic vessels were isolated from living embryos. Exogenous d-glucose and l-glucose caused increased plasma d-glucose levels, increased plasma alanine aminotransferase (ALT) activities, and decreased embryo viability. Embryo viability was monitored by a reduction in the percentage of living embryos at theoretical stage 44, reduced embryo masses, reduced brain masses, and reduced liver masses. When compared to controls, embryonic exposure to either exogenous d-glucose or l-glucose caused increased caspase-3 activities and increased lipid hydroperoxide (LPO) levels in both brain and liver tissues. Because lipid hydroperoxides are lipid peroxidation intermediates that result in the attack of any unsaturated neutral lipid or unsaturated phospholipid, the effect of exogenous glucose on hepatic membrane fatty acid composition was studied. Exogenous glucose (either d-glucose or l-glucose) promoted reduced levels of several unsaturated, long-chain fatty acids and increased levels of saturated, short-chain fatty acids within hepatic membranes. Exogenous-glucose induced decreases in the ratios of unsaturated/saturated fatty acids and long-chain/short-chain fatty acids within hepatic membranes which strongly correlated with glucose-induced increases in plasma ALT activities and moderately correlated to hepatic LPO levels. These observations are consistent with the hypothesis that embryonic hyperglycemia promotes hepatic membrane lipid peroxidation and hepatic cell death.
Comp Biochem Physiol B Biochem Mol Biol 2005 Jul
PMID:Hyperglycemia-induced changes in hepatic membrane fatty acid composition correlate with increased caspase-3 activities and reduced chick embryo viability. 1590 50

Mercury is a highly toxic metal which induces oxidative stress. Superoxide dismutases, catalase, and glutathion peroxidase are proteins involved in the endogenous antioxidant defence system. In the present study rats were administered orally, by gavage, a single daily dose of HgCl2 for three consecutive days. In order to find a relation between the proteins involved in the antioxidant defence and mercury intoxication, parameters of liver injury, redox state of the cells, as well as intracellular protein levels and enzyme activities of Mn-dependent superoxide dismutase (MnSOD), Cu-Zn-dependent superoxide dismutase (CuZnSOD), catalase, and glutathione peroxidase (GPx) were assayed both in blood and in liver homogenates. HgCl2 at the doses of 0.1 mg/kg produced liver damage which that was detected by a slight increase in serum alanine aminotransferase and gamma glutamyl transferase. Hepatic GSH/GSSG ratio was assayed as a parameter of oxidative stress and a significant decrease was detected, as well as significant increases in enzyme activities and protein levels of hepatic antioxidant defence systems. Changes in both MnSOD and CuZnSOD were parallel to those of liver injury and oxidative stress, while the changes detected in catalase and GPx activities were progressively increased along with the mercury intoxication. Other enzyme activities related to the glutathione redox cycle, such as glutathione reductase (GR) and glucose-6-phosphate dehydrogenase (G6PDH), also increased progressively. We conclude that against low doses of mercury that produce a slight oxidative stress and liver injury, the response of the liver was to induce the synthesis and activity of the enzymes involved in the endogenous antioxidant system. The activities of all the enzymes assayed showed a rapidly induced coordinated response.
J Biochem Mol Toxicol 2005
PMID:Endogenous antioxidant defence system in rat liver following mercury chloride oral intoxication. 1597 96


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