Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.6.1.2 (alanine aminotransferase)
 26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sublethal doses of vincristine (VNC) and bacterial lipopolysaccharide (LPS) administered simultaneously to adult male mice resulted in markedly enhanced mortality. All of 10 strains of Pseudomonas aeruginosa tested, 4 of 7 strains of Bacteroides, and 6 of 10 strains of Listeria monocytogenes were able to substitute for purified LPS in enhancing mortality in VNC-treated mice. Inoculation of mice with each of 10 strains of Pseudomonas, each of 7 strains of Bacteroides, and about half of the 10 strains of Listeria tested elicited increased resistance to the lethal action of purified LPS. The patterns of responses of mice receiving a lethal combination of 2 mg of LPS/kg and 1 mg of VNC/kg resembled those of mice receiving a lethal dose of 10 mg of VNC/kg alone or 15 mg of LPS/kg alone with respect to (i) serum glutamic pyruvate transaminase activity, (ii) hematocrit values, and (iii) thrombocytopenia. The patterns of responses of mice receiving a lethal combination of LPS and VNC resembled those of mice receiving a lethal dose of LPS alone with respect to (i) hypothermia, (ii) retention of sulfobromophthalein, (iii) fibrinogen level, (iv) prothrombin activity, (v) blood urea nitrogen levels, and (vi) time of death. These data are consistent with the proposition that the combination of VNC and LPS produces a fatal renal failure. Histological studies confirmed that there was extensive renal damage in mice treated with lethal doses of LPS alone or a lethal combination of LPS and VNC.
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PMID:Enhanced toxicity for mice of combinations of bacterial lipopolysaccharide and vincristine. 94 80

To investigate the role of Kupffer cells in complement activation, we used a rat model of acute hepatic injury induced by D-Galactosamine (GalN) and lipopolysaccharide (LPS). In in vivo study, minimal histological changes were observed after i.p. GalN (200 mg/kg) single administration. Complement hemolytic activity (CH 50) decreased to 70% of its initial value 2-3 h after i.p. LPS (1.5 mg/kg) single administration. Massive hepatic necrosis was induced by simultaneous administration of GalN and LPS. After 2-3 h, CH 50 decreased to 70% of its initial value, and deposition of C3 fluorescence (C3) was observed in Kupffer cells. After 4 h, GPT was greatly increased (1286 +/- 240 IU/l), CH 50 was further reduced, and C3 was observed on hepatocyte membranes and in the cytosol. In in vitro study, we used hepatocyte cultures and co-cultures of hepatocytes and Kupffer cells to investigate the participation of GalN, LPS, complement, and Kupffer cells in hepatic cell necrosis. We found no increase of LDH (% leakage) when LPS and complement were added to the medium (22.7 +/- 5.7%). A moderate increase was observed with the addition of GalN (33.2 +/- 2.6%). A remarkable increase was observed only with the addition of GalN, LPS, and complement to the co-culture (50.0 +/- 8.8%). These results suggest that Kupffer cells activated by LPS are very important in promoting acute hepatic injury by complement.
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PMID:The role of Kupffer cells in complement activation in D-Galactosamine/lipopolysaccharide-induced hepatic injury of rats. 144 56

Role of platelet-activating factor (PAF) as a potential mediator of hepatic pathophysiology was investigated using a rat model of obstructive jaundice. Over a 1-wk course of bile duct ligation, a sixfold increase in tissue levels of PAF (1.57 +/- 0.43 ng/g vs. control 0.24 +/- 0.08 ng/g) occurred in the liver, whereas no change was observed in PAF levels in plasma. Concomitantly, endotoxin was detected in portal blood drawn from jaundiced rats, and antagonism of the putative effect of endotoxin by neomycin plus polymyxin B reduced local PAF concentrations in livers from jaundiced animals. Induction of neutropenia failed to alter the elevated hepatic PAF concentrations. Moreover, a large quantity of PAF was released spontaneously from Kupffer cells isolated from livers derived from jaundiced rats but not from endothelial cells or hepatocytes from the same animals. An in vitro study using cultured Kupffer cells from normal rats indicated that Kupffer cells secreted a significant amount of PAF in response to lipopolysaccharide challenge; pretreatment of cells with polymyxin B prevented this stimulated PAF release. Treatment of animals with either of two PAF receptor antagonists (BN 52021 and WEB 2170) partially prevented the increase in tissue levels of eicosanoids and O2-derived free radicals and partially alleviated liver injury as judged by the appearance of glutamate-pyruvate transaminase in the plasma of jaundiced rats. The present study indicates 1) that endogenous PAF may be an important signaling mediator for the hepatic inflammatory alterations associated with short-term bile duct ligation and 2) that the interaction of Kupffer cells with portal endotoxin is the mechanism by which PAF is produced locally.
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PMID:Role of platelet-activating factor in hepatic responses after bile duct ligation in rats. 144 33

Lead markedly augments the lethality of endotoxin lipopolysaccharide (LPS) in rats. In this model of LPS toxicity, the liver is severely injured. Much of the tissue injury produced by LPS is thought to be mediated by the cytokine tumor necrosis factor (TNF). Tumor necrosis factor recently has been speculated to be a mediator of several models of liver injury such as that produced by galactosamine. To investigate the possible role of TNF in the lead-enhanced LPS toxicity model, we administered doses of lead acetate (15 mg/kg), LPS (100 micrograms/kg), or TNF (6.25 x 10(6) U/kg) that produced minimal changes in liver enzymes. However, when lead was administered simultaneously with either LPS or TNF, serum aspartate transaminase, alanine transaminase, alkaline phosphatase, glutamyl transpeptidase, and plasma triglyceride levels were markedly increased. Lead + LPS treatment increased both peak serum TNF concentrations and TNF "area under the curve" as compared with LPS alone. We conclude that lead not only enhances LPS lethality but also LPS liver injury. Furthermore, lead enhances TNF liver injury and increases LPS-stimulated serum TNF levels. These data suggest that the lead-enhanced LPS model offers a system for studying TNF-induced liver injury.
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PMID:Lead enhances lipopolysaccharide and tumor necrosis factor liver injury. 167 39

When guinea pigs sensitized with trinitrophenylated (TNPed) liver protein 1 (LP1) were intravenously injected with TNPed isolated hepatocytes, remarkable hepatic cell injury was induced 24 hours later. In this experimental model, drug-induced allergic liver injury was induced by using trinitrobenzen sulfonic acid (TNBS) as the hapten and LP1 as the carrier. When these sensitized guinea pigs were intravenously injected with 10 micrograms of lipopolysaccharide (LPS) along with TNPed isolated hepatocytes, serum AST and ALT levels were remarkably higher than those of the guinea pigs not injected with LPS. Hepatic cell necrosis was also more extensive, and some bleeding was observed. Although none of the guinea pigs died even after 24 hours, when 50 micrograms of LPS was injected, many of the guinea pigs started to die and the survival rate was 5% at 24 hours. These results suggested that LPS enhanced liver injury in this experimental drug-induced allergic liver injury model.
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PMID:The enhancement of liver injury by lipopolysaccharide in an experimental drug-induced allergic hepatitis model. 221 Feb 19

Intravenous injection of lipopolysaccharide and D-galactosamine, at doses of 0.2 micrograms/kg and 800 mg/kg, respectively, elicited massive hepatic necrosis within 24 hr in C3H/HeN mice. The plasma L-alanine aminotransferase (ALT, E.C. 2.6.1.2) or L-aspartate aminotransferase (AST, E.C. 2.6.1.1) activities at this point reached more than 2,000 IU/L. However, overt hepatic injury as evaluated by the plasma aminotransferase activities did not develop in mice in which only lipopolysaccharide or only D-galactosamine was injected. No tumor necrosis factor-like activities could be detected in the plasma of galactosamine- and lipopolysaccharide-injected mice as determined by the assay of cytotoxicity to highly tumor necrosis factor-sensitive L-P3 cells through the experimental period of 24 hr. However, passive immunization against mouse tumor necrosis factor-alpha with polyvalent rabbit anti-mouse tumor necrosis factor-alpha antiserum, which was able to neutralize the cytotoxic effects of recombinant mouse tumor necrosis factor-alpha on L-P3 cells, could protect the mice from the development of hepatic injury in a dose-dependent manner. Simultaneous injection of recombinant human tumor necrosis factor-alpha, instead of lipopolysaccharide, with 800 mg/kg of D-galactosamine in lipopolysaccharide-resistant C3H/HeJ mice sensitized the animals more than one thousand-fold to the development of hepatic injury. The livers appeared to be morphologically similar to those of galactosamine- and lipopolysaccharide-injected C3H/HeN mice.
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PMID:Involvement of tumor necrosis factor-alpha in development of hepatic injury in galactosamine-sensitized mice. 222 17

The effects of OKY-046, a selective thromboxane A2 (TXA2) synthetase inhibitor, and ONO-3708, a novel TXA2 receptor antagonist, on liver disease were investigated in mice. The liver injury was induced by either an injection of antibasic liver protein (BLP) antibody into DBA/2 mice that had been previously immunized with rabbit IgG or by an injection of bacterial lipopolysaccharide (LPS) into Corynebacterium parvum (C. parvum) pretreated DDY mice. 1) In both injury models, clear elevation of glutamate transaminase (GOT and GPT) activity due to extensive liver parenchymal cell damage was observed; this was confirmed by significant histopathological changes in the liver. 2) Typical histopathological changes in the liver were submassive hepatocellular necrosis in the anti-BLP antibody-induced injury model and focal necrosis in the LPS-induced model. Inflammation and increased cell infiltration in portal connective tissue were observed in both cases. 3) Administration of OKY-046 (50 mg/kg) and ONO-3708 (0.5, 1.0 and 2.0 mg/kg) suppressed the elevation of serum GOT and GPT levels and histopathological changes in both experimental liver injury models. 4) Indomethacin inhibited the development of liver disease caused by anti-BLP antibody but not by bacterial LPS. Prostaglandin I2 inhibited the elevation of serum GOT and GPT levels and histopathological changes of the liver in the mice treated with anti-BLP antibody and showed the tendency to inhibit the development of liver injury caused by bacterial LPS.
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PMID:Effect of OKY-046 and ONO-3708 on liver injury in mice. 251 4

The role of peptide leukotrienes (p-LTs), especially LTC4 and LTD4 in liver disease, was investigated in mice experimental liver injury models. The liver injury was induced by the injection of bacterial lipopolysaccharide (LPS) into Corynebacterium parvum pretreated mice. Carbon tetrachloride (CCl4)-induced liver injury in mice was used as a standard model. In both injury models, extensive liver parenchymal cell damage was observed by the elevation of glutamate transaminase (GOT and GPT) activity and confirmed by significant histopathological changes in the liver. Moreover, significant elevation of LTC4 in the liver was observed in both models 1 and 6 h after the onset of disease. Administration of AA-861, a selective 5-lipoxygenase inhibitor (0.5, 1, and 2 mg/kg) and LY-171883, a p-LT receptor antagonist (50 and 200 mg/kg) suppressed the elevation of serum GOT and GPT levels and histopathological changes in both experimental liver injury models. In addition, when authentic LTC4 or LTD4 was injected into the mouse, clear elevation of serum GOT and GPT and histopathological changes of the liver were observed. These results suggest that p-LTs play a role in the onset of liver diseases in mice.
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PMID:Role of peptide-leukotrienes in liver injury in mice. 257

The hepatoprotective effect of Gomisin A (TJN-101), which is a lignan compound isolated from Schizandra fruits, was studied on three immunologic liver injury models in mice. The first liver injury model was produced by the injection of anti-basic liver protein (BLP) antibody into DBA/2 mice which had been previously immunized with rabbit IgG (RGG). Other models were effected by injection of anti-liver specific protein (LSP) antibody into DBA/2 mice or by the injection of bacterial lipopolysaccharide (LPS) into ddY mice pretreated with Corynebacterium parvum (C. parvum). TJN-101 inhibited the elevation of transaminase (GOT and GPT) activities and showed the tendency to inhibit the histopathological changes of the liver in all models. Moreover, TJN-101 inhibited deoxycholic acid-induced release of transaminase from cultured rat hepatocytes in vitro, but did not affect the formation of hemolytic plaque forming cells in immunized mice spleens and hemolytic activity of guinea pig complement in immunohemolysis reaction. These results, therefore, suggested that the hepatoprotective effect of TJN-101 could be related to the protecting effect of hepatocyte plasma membrane rather than the inhibiting effects of the antibody formation and complement activity.
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PMID:The effect of gomisin A on immunologic liver injury in mice. 271 84

The effects of carbon tetrachloride (CCl4), following 7 consecutive days of exposure ip at 500, 1000, and 1500 mg/kg, were determined on murine humoral and cell-mediated immune responses, body and organ weights, spleen cell blastogenesis following mitogenic stimulation, and clinical serum parameters for liver injury. In vivo sensitization of CCl4-treated B6C3F1 mice resulted in a dose-dependent suppression of the T-dependent antibody response to sheep red blood cells (sRBC) at all doses--36, 48, and 53%, respectively. The T-independent in vivo antibody response to DNP-Ficoll was suppressed only at 1500 mg/kg, and only by approximately 16%. This dosing regimen also resulted in a significant decrease in thymus weights; however, there were no significant effects on liver, kidney, lung, or body weights. The serum chemistry profile indicated a dose-dependent increase in serum glutamic-pyruvic transaminase (SGPT) levels (34-, 47-, and 55-fold) and a non-dose-dependent increase in serum bilirubin and total protein. Serum glucose and albumin levels were unaffected. Splenocytes from mice treated with 1500 mg/kg and sensitized in vitro with antigen demonstrated a comparably suppressed antibody response to the antigens sRBC and DNP-Ficoll as observed in vivo--66 and 28% respectively. This dose of CCl4 had no effect on the in vitro antibody response to the polyclonal antigen lipopolysaccharide. The mixed lymphocyte response was dose dependently suppressed following CCl4 exposure; however, the delayed-type hypersensitivity response was unaffected. Lymphocyte blastogenesis following mitogenic stimulation with lipopolysaccharide or concanavalin A was also inhibited by CCl4 exposure. These studies demonstrate that exposure to CCl4 results in a marked suppression in both humoral and cell-mediated immune responses at concentrations which also affect the liver as evidenced by the marked increase in SGPT levels.
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PMID:Suppression of humoral and cell-mediated immune responses by carbon tetrachloride. 292 10


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