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)

Hepatocyte growth factor (HGF) has a potent antiapoptotic effect on hepatocytes in D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-treated rats. Here, we report that adenovirus mediated HGF gene transfer into liver prevents liver failure and reduces mortality of rats treated with d-GalN/LPS. Fisher 344 rats, which were given intraperitoneal injections of pAxCAHGF 48 h before, were treated with D-GalN/LPS. Serum ALT in the HGF group at 6 and 12 h after D-GalN/LPS was decreased to 1/6 and 1/12 of the control group (P < 0.01, each). Concomitant reduction of apoptotic cells were also observed. The Kaplan-Meier analysis showed that a survival rate in the HGF group was improved, compared to that in the control group (P < 0.05). Caspase-3 activity in the HGF group decreased, compared to that in the control group, especially at 12 h (P < 0.05), although it maintained a high level in the control group. Expression of Bcl-xL and cyclooxygenase-2 (Cox-2) was induced in liver by HGF gene transfer. These data suggest that HGF exerts an antiapoptotic effect through dual induction of Bcl-xL and Cox-2, which suppresses caspase-3 activity.
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PMID:Adenovirus-mediated hepatocyte growth factor gene transfer prevents lethal liver failure in rats. 1109 40

We have previously demonstrated that after bile duct ligation hepatocytes express Bcl-2, although the mechanisms regulating Bcl-2 expression were not identified. Our aim was to determine if biliary constituents induce hepatocellular expression of Bcl-2 by a cyclooxygenase-2 (COX-2)-dependent mechanism. We used the choledocho-venous fistula (CVF) rat model for these studies and inhibited COX-2 by feeding the animals nimesulide, a selective inhibitor of COX-2 activity. Serum bile acids were 70-fold greater in CVF animals compared with controls, although liver histology and serum alanine aminotransferase values remained normal for the duration of the study. Neither Bcl-2 nor COX-2 was detected in sham-operated animals. However, Bcl-2 was expressed in hepatocytes but not in other liver cells in the CVF animals. In contrast, COX-2 protein was identified in Kupffer cells but not in hepatocytes of CVF animals. Hepatic Bcl-2 protein expression was fourfold lower in the livers from nimesulide-treated CVF rats. In conclusion, high circulating concentrations of biliary constituents are associated with stimulation of de novo hepatocyte expression of Bcl-2 and Kupffer cell expression of COX-2. These data suggest Kupffer cell-derived prostanoids may regulate Bcl-2 expression in the hepatocyte.
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PMID:Kupffer cell-derived cyclooxygenase-2 regulates hepatocyte Bcl-2 expression in choledocho-venous fistula rats. 1129 87

Bacterial endotoxin (lipopolysaccharide; LPS) augments the hepatotoxicity of a number of xenobiotics including allyl alcohol. The mechanism for this effect is known to involve the inflammatory response elicited by LPS. Upregulation of cyclooxygenase-2 (COX-2) and production of eicosanoids are important aspects of inflammation, therefore studies were undertaken to investigate the role of COX-2 in LPS-induced enhancement of liver injury from allyl alcohol. Rats were pretreated (iv) with a noninjurious dose of LPS or sterile saline vehicle and 2 h later were treated (ip) with a noninjurious dose of allyl alcohol or saline vehicle. COX-2 mRNA was determined by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR), and liver injury was assessed from activities in serum of alanine and aspartate aminotransferases (ALT and AST, respectively) and from histology. Liver injury was observed only in rats cotreated with LPS and allyl alcohol. Serum ALT activity was increased by 4 h after administration of LPS and continued to increase through 8 h. COX-2 mRNA was detectable at low levels in livers from rats receiving only the vehicles at any time up to 8 h. Expression of COX-2 mRNA was increased by 30 min after administration of LPS and remained elevated through 6 h. Allyl alcohol treatment alone caused an increase in COX-2 mRNA at 4 h (2 h after allyl alcohol) that lasted less than 2 h. In livers from rats cotreated with LPS and allyl alcohol, levels of COX-2 mRNA were greater than levels seen with either LPS or allyl alcohol alone. The increased expression of COX-2 mRNA was accompanied by an increase in the concentration of prostaglandin (PG) D(2) in plasma. Plasma PGD(2) concentration was increased to a greater extent in rats treated with LPS plus allyl alcohol compared to allyl alcohol or LPS alone. Pretreatment with the COX-2 selective inhibitor, NS-398, abolished the increase in plasma PGD(2) and reduced the increase in ALT and AST activities observed in rats cotreated with LPS and allyl alcohol. NS-398 did not affect liver injury from allyl alcohol alone administered at a larger, hepatotoxic dose. In addition, ibuprofen, a nonselective inhibitor of cyclooxygenases, did not protect against liver injury from LPS plus allyl alcohol. In isolated hepatocytes PGD(2), but not PGE(2), reduced the concentration of allyl alcohol required to cause half-maximal cytotoxicity. These results suggest that products of COX-2 play a role in the augmentation of allyl alcohol-induced liver injury by LPS.
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PMID:Involvement of cyclooxygenase-2 in the potentiation of allyl alcohol-induced liver injury by bacterial lipopolysaccharide. 1144 26

Administration of pyruvate, an effective scavenger of reactive oxygen species, has been shown to be salutary in numerous models of redox-mediated tissue or organ injury. Pyruvate, however, is unstable in solution and, hence, is not attractive for development as a therapeutic agent. Herein, ethyl pyruvate, which is thought to be more stable than the parent compound, was formulated in a calcium-containing balanced salt solution [Ringer ethyl pyruvate solution (REPS)] and evaluated in a murine model of hemorrhagic shock and resuscitation (HS/R). Resuscitation with REPS instead of Ringer lactate solution (RLS) significantly improved survival at 24 h and abrogated bacterial translocation to mesenteric lymph nodes and the development of increased ileal mucosal permeability to FITC-labeled dextran (4,000 Da) at 4 h. Mice treated with REPS instead of RLS also had lower circulating levels of alanine aminotransferase at 4 h. Treatment with REPS instead of RLS decreased activation of nuclear factor-kappaB in liver and colonic mucosa after HS/R and also decreased the expression of inducible nitric oxide synthase, tumor necrosis factor, cyclooxygenase-2, and interleukin-6 mRNA in liver, ileal mucosa, and/or colonic mucosa. These data support the view that resuscitation with REPS modulates the inflammatory response and decreases hepatocellular and gut mucosal injury in mice subjected to HS/R.
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PMID:Ethyl pyruvate modulates inflammatory gene expression in mice subjected to hemorrhagic shock. 1206 9

The gastrointestinal tolerability of metamizol and acetaminophen [weak cyclooxygenase (COX) inhibitors] in comparison with diclofenac (nonselective cyclooxygenase inhibitor) was evaluated in subchronic treatments in rats. Wistar rats received 60 mg/kg body weight of metamizol and acetaminophen, and 3 mg/kg body weight of diclofenac by oral route twice daily for 14 days. Myeloperoxidase activity, an index of neutrophil infiltration, COX expression and the effects on blood parameters used as indicators of liver and renal functions were also studied. Metamizol and acetaminophen did not cause apparent gastrointestinal lesions; in contrast diclofenac showed swelling and an increased thickness on the distal intestinal mucosa. Myeloperoxidase activity was significantly increased in the small bowel with diclofenac treatment. In gastric mucosa the expression of the cyclooxygenase-1 was not affected and the expression of cyclooxygenase-2 was not observed. Diclofenac treatment significantly diminished hematocrit, hemoglobin, and corpuscular volume and increased the number of platelets. Aspartate aminotransferase and gamma-glutamyltransferase activity were also altered and, regarding the renal biochemical parameters, the animals treated with diclofenac had increased urea values. In contrast, acetaminophen treatment did not affect either of these parameters and metamizol increased only the alanine aminotransferase activity. Under our experimental conditions, metamizol and acetaminophen seem to be safe drugs. In contrast, with diclofenac treatment blood loss and anemia are observed which could stem from the small intestinal injury. Moreover, this drug could to impair kidney function.
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PMID:Gastrointestinal tolerability of metamizol, acetaminophen, and diclofenac in subchronic treatment in rats. 1249 3

This study was designed to investigate the effect of Trolox, a hydrophilic analogue of vitamin E, on the alteration of vasoregulatory gene expression during hepatic ischemia and reperfusion (I/R). Rats were subjected to 60 min of hepatic ischemia in vivo. The rats were treated intravenously with Trolox (2.5 mg/kg) or the vehicle as a control 5 min before reperfusion. Liver samples were obtained 5 h after reperfusion for a RT-PCR analysis on the mRNA for the genes of interest. These mRNA peptides are endothelin-1 (ET-1), potent vasoconstrictor peptide, its receptor ET(A) and ET(B), vasodilator endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), heme oxygenase-1 (HO-1), tumor necrosis factor-alpha (TNF-alpha) and cyclooxygenase-2 (COX-2). It was seen that serum alanine aminotransferase and lipid peroxidation levels were markedly increased after I/R and Trolox significantly suppressed this increase. In contrast, the glutathione concentration decreased in the I/R group, and this decrease was inhibited by Trolox. ET-1 mRNA expression was increased by I/R, an increase which was prevented by Trolox. The mRNA levels for ET(A) receptor was significantly decreased, whereas ET(B) receptor transcript increased in the I/R group. The increase in ET(A) was prevented by Trolox. The mRNA levels for iNOS and HO-1 significantly increased in the I/R group and Trolox attenuated this increase. There were no significant differences in eNOS mRNA expression among any of the experimental groups. The mRNA levels for COX-2 and TNF-alpha significantly increased in I/R group and Trolox also attenuated this increase. Our findings suggest that I/R induces an imbalanced hepatic vasoregulatory gene expression and Trolox ameliorates this change through its free radical scavenging activity.
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PMID:Effect of Trolox on altered vasoregulatory gene expression in hepatic ischemia/reperfusion. 1502 26

Selective inhibitors of cyclooxygenase-2 have less gastroduodenal toxicity than non selective anti-inflammatory drugs. However, there is little information on their effect on the distal gut. A 91 year old woman presented with acute diarrhoea 5 weeks after beginning celecoxib treatment. Laboratory results showed an inflammatory syndrome and increased alanine aminotransferase (ALT) to 13 N. Endoscopic examination of the colon showed diffuse erythematous lesions of the sigmoid and of part of the right colon. No aetiology has been found for colitis or hepatitis. Diarrhea and blood test anomalies disappeared one week after celecoxib was stopped. The role of celecoxib in the etiology of colitis was considered plausible but not for liver damage. This report and a few other cases in the literature suggest that cyclooxygenase-2 selective non-steroidal anti-inflammatory drug inhibitor toxicity should be investigated in case of unexplained acute colitis.
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PMID:[Acute colitis closely following the beginning of celecoxib treatment]. 1651 92

Increased hepatic abnormality has been observed in patients with systemic lupus erythematosus (SLE) and contributes to the elevated apoptosis that results in severe disease activity. Since cystamine has been demonstrated to be beneficial for NZB/W F1 mice, this study investigates the effects of cystamine on various inflammatory and stress-related proteins in liver from NZB/W F1 mice. Nephelometric analyses and immunoblots were conducted to detect aspartate aminotransferase (AST), alanine aminotransferase (ALT), C-reactive protein (CRP), p53, p21, Gadd45, heat shock protein 70 (HSP70) and cyclooxygenase-2 (COX-2). AST and ALT were reduced in NZB/W F1 mice that were given cystamine and CRP, p53, p21, Gadd45, HSP70 and COX-2 proteins in the liver were reduced in NZB/W F1 mice that were treated with cystamine. Moreover, cystamine has no obvious effect on BALB/c mice. These findings suggest that cystamine reduces the inflammation in liver of NZB/W F1 mice and provide a clue in treatment of SLE with liver abnormality.
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PMID:Transglutaminase inhibitor cystamine alleviates the abnormality in liver from NZB/W F1 mice. 1803 33

Previous studies have shown that injury initiated by toxicants progresses even after most of the toxicant is eliminated from the body. One mechanism of progression of injury is the extracellular appearance of hydrolytic enzymes following leakage or upon cell lyses. Under normal conditions, after exposure to low to moderate doses of toxicants, secretory phospholipase A(2) (sPLA(2)) and other hydrolytic enzymes are known to appear in the extracellular spaces in order to cleanup the post-necrotic debris in tissues. We tested the hypothesis that sPLA(2) contributes to progression of toxicant-initiated liver injury because of hydrolysis of membrane phospholipids of hepatocytes in the perinecrotic areas in the absence of sufficient cyclooxygenase-2 (COX-2). Male Sprague-Dawley rats were administered either a moderately hepatotoxic dose (MD, 2 ml CCl(4)/kg, ip) or a highly hepatotoxic dose (HD, 3 ml CCl(4)/kg, ip) of CCl(4). After MD, liver sPLA(2) and COX-2 were co-localized in the necrotic and perinecrotic areas and their activities in plasma and liver increased before decreasing in tandem with liver injury (ALT and histopathology) leading to 100% survival. In contrast, after the HD, high extracellular and hepatic sPLA(2) activities were accompanied by minimal COX-2 activity and localization in the liver throughout the time course. This led to progression of liver injury and 70% mortality. These data suggested a destructive role of sPLA(2) in the absence of sufficient COX-2. Time- and dose-dependent destruction of hepatocytes by sPLA(2) in isolated hepatocyte incubations confirmed the destructive ability of sPLA(2) when present extracellularly, suggesting its ability to spread injury in vivo. These findings suggest that sPLA(2), secreted for cleanup of necrotic debris upon initiation of hepatic necrosis, requires the co-presence of sufficiently induced COX-2 activity to prevent the run-away destructive action of sPLA(2) in the absence of the tissue protective mechanisms afforded by COX-2 induction.
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PMID:Secretory phospholipase A2 mediates progression of acute liver injury in the absence of sufficient cyclooxygenase-2. 1832 82

Lipopolysaccharide (LPS) causes hepatic injury that is mediated, in part, by upregulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Ketamine has been shown to prevent these effects. Because upregulation of heme oxygenase-1 (HO-1) has hepatoprotective effects, as does carbon monoxide (CO), an end product of the HO-1 catalytic reaction, we examined the effects of HO-1 inhibition on ketamine-induced hepatoprotection and assessed whether CO could attenuate LPS-induced hepatic injury. One group of rats received ketamine (70 mg/kg ip) or saline concurrently with either the HO-1 inhibitor tin protoporphyrin IX (50 micromol/kg ip) or saline. Another group of rats received inhalational CO (250 ppm over 1 h) or room air. All rats were given LPS (20 mg/kg ip) or saline 1 h later and euthanized 5 h after LPS or saline. Liver was collected for iNOS, COX-2, and HO-1 (Western blot), NF-kappaB and PPAR-gamma analysis (EMSA), and iNOS and COX-2 mRNA analysis (RT-PCR). Serum was collected to measure alanine aminotransferase as an index of hepatocellular injury. HO-1 inhibition attenuated ketamine-induced hepatoprotection and downregulation of iNOS and COX-2 protein. CO prevented LPS-induced hepatic injury and upregulation of iNOS and COX-2 proteins. Although CO abolished the ability of LPS to diminish PPAR-gamma activity, it enhanced NF-kappaB activity. These data suggest that the hepatoprotective effects of ketamine are mediated primarily by HO-1 and its end product CO.
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PMID:Ketamine-induced hepatoprotection: the role of heme oxygenase-1. 1937 6


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