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)

An animal model of hepatocytic necrosis was established with injection of D-galactosamine into peritoneal cavity. Examination at regular intervals after injection showed that the level of increased serum TB, ALT and GST and the degree of histological changes in the liver were less marked in PGE-treated animals (n = 34) than those in PGE-untreated animals (n = 29), suggesting that PGE has definite protective effect for experimental hepatocytic necrosis. According to severity of the condition hepatic failure was divided into early stage, typical stage and late stage. A treatment group of 55 cases received PGE1 therapy and a control group basic support therapy only. The results showed that difference of the total effective rate was not significant between the two groups, but in the early stage of hepatic failure, the effective rate in the treatment group was markedly higher than that in the control group. In addition, incidence of hepato-renal syndrome was lower in the treatment group. We are of the opinion that division of severe viral hepatitis into three stages for evaluation of therapeutic effect is rational and useful and early use of PGE1 may show certain efficacy.
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PMID:[Protective effect of prostaglandin E on hepatocytes and its value of early treatment of severe viral hepatitis]. 203 89

Based on the relationship between in vivo disposition of macromolecules and their physicochemical and biological characteristics obtained through clearance concept-based pharmacokinetic analysis, polymeric prodrugs of prostaglandin E(1)(PGE(1)) were designed stepwise and evaluated on their targeting and therapeutic efficiencies. First poly-L-lysine (PLL) and poly-L-glutamic acid (PLGA) with an ethylenediamine (ED) spacer were modified with 2-imino-2-methoxyethyl 1-thiogalactoside to obtain galactosylated derivatives. After intravenous injection in mice, Gal-ED-PLGA was selectively taken up by the liver parenchymal cells via receptor-mediated endocytosis, while Gal-PLL accumulated in the liver as well as PLL mostly due to electrostatic interaction. Although Gal-ED-PLGA showed good targeting efficacy, its PGE(1) conjugate synthesized with activated PGE(1) by carbonyldiimidazole method failed to show therapeutic effects probably due to inactivation of PGE(1) during conjugation and lack of release in the tissue. In order to overcome these problems, we next conjugated PGE(1) to galactosylated poly-(L-glutamic acid) hydrazide (Gal-HZ-PLGA) in which PGE(1) was easily coupled to Gal-HZ-PLGA via a hydrazone bond in weak acidic solution (pH 5) at room temperature. The PGE(1)-Gal-HZ-PLGA conjugate labeled with [(111)In] or [(3)H]PGE(1) rapidly accumulated in the liver parenchymal cells. In addition, the PGE(1) conjugate effectively inhibited the increase of the GPT level in plasma, while free PGE(1) indicated no therapeutic efficacy even at more than ten times higher doses, in carbon tetrachloride-induced hepatitis mice. These findings suggest potentials of polymeric targeting systems of PGE(1) to hepatocyte utilizing galactose recognition.
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PMID:Design of polymeric prodrugs of prostaglandin E(1) having galactose residue for hepatocyte targeting. 1051 58

Prostaglandin E(1) (PGE(1) ) was incorporated in galactosylated liposomes containing cholesten-5-yloxy-N-(4-((1-imino-2-beta-D-thiogalactosyle thyl)amino)b utyl)formamide (Gal-C4-Chol) intended for hepatocyte-selective delivery. Liposomes composed of distearoylphosphatidylcholine (DSPC)/cholesterol (Chol)/Gal-C4-Chol (60∶35∶5) were prepared and compared with DSPC/Chol (60∶40) liposomes. After intravenous injection of [(3) H]-labeled PGE(1) or cholesteryl hexadecyl ether (CHE) with the liposomal formulation, mice were sacrificed at a series of times, and the radioactivity in tissues was determined. Up to about 80% of [(3) H]CHE in galactosylated liposomes had accumulated in the liver 10 min after intravenous injection and the liver accumulation of the incorporated [(3) H]PGE(1) was significantly higher than that in control liposomes during the entire test period. The pharmacological activity was examined in mice with fulminant hepatitis induced by peritoneal injection of carbon tetrachloride. Intravenous injection of PGE(1) incorporated in DSPC/Chol/Gal-C4-Chol (60∶35∶5) liposomes significantly suppressed the GPT increase, whereas PGE(1) (dissolved in saline) and PGE(1) incorporated in DSPC/Chol (60∶40) liposomes had little effect.
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PMID:Targeted delivery of prostaglandin E1 to hepatocytes using galactosylated liposomes. 1093 23

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

The aim of the present study was to evaluate the effect of ursodeoxycholic acid (UDCA) on prostaglandin and fatty acid metabolism and the possible relation of these substances to the development of alcoholic fatty liver in rats. The effects of UDCA (40 mg/kg/day, 30 days) were studied in rats pair-fed a high-fat diet (52% of calories as fat) with daily ethanol (4 g/kg/day, 30 days) intragastric intubation. The livers of ethanol-treated animals were characterized by fatty dystrophy. Liver triglyceride and cholesterol ester contents and the activities of serum marker enzymes, alanine aminotransferase and gamma-glutamyltransferase, were significantly increased. Ethanol enhanced phosphoinositol and sphingomyelin content in liver microsomes and lowered prostaglandin E(2) (PGE(2)) concentration in the liver. An increase in the percentage of monoenoic fatty acids and a decrease in the n-6 acid family in liver phospholipids, linoleoyl-CoA desaturase, and PGE(2) synthase activities in liver microsomes were observed in ethanol-treated rats. Treatment with UDCA improved liver morphologic characteristics, decreased triglyceride and cholesterol ester contents, increased the PGE(2) level, and normalized linoleoyl-CoA desaturase and PGE(2) synthase activities, as well as phospholipid and fatty acid patterns in the liver. The activities of the serum marker enzymes were decreased in the ethanol- and UDCA-treated group. Ursodeoxycholic acid lowered the viscosity of the microsomal membrane, as assessed by both fluorescence probe techniques and the saturated/unsaturated fatty acid ratio. We propose that the hepatoprotective effect of UDCA in alcoholic fatty liver is related to the stabilization of microsomal membranes, the prevention of a decrease in essential fatty acids and PGE(2) in the liver, and, probably, an improvement in biochemical processes controlled by PGE(2).
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PMID:Effect of ursodeoxycholic acid on prostaglandin metabolism and microsomal membranes in alcoholic fatty liver. 1174 79

In two cases of hepatic arterial flow interruption after hepatopancreatic surgery, continuous PGE(1) infusion from the superior mesenteric artery (SMA) was applied to oxygenate the liver through the portal vein. Case 1 was a 69-year-old woman with a non-functioning islet cell tumor of the pancreas. She underwent pancreatic resection following hepatic arterial infusion of anticancer drugs. Serum alanine aminotransferase (ALT) was elevated to 5500 IU/l on postoperative day (POD) 2; angiography revealed complete celiac artery obstruction. Continuous PGE(1) was administered from SMA at a rate of 0.01 &mgr;g/kg/min for 7 days. Serum ALT was normalized within 2 weeks and the peak level of serum total bilirubin (T. Bil) was 4.5 mg/dl. Case 2 was a 66-year-old man suffering from metastatic liver cancer. Complete obstruction of the proper hepatic artery was noted at the time of liver resection after hepatic arterial chemotherapy. Serum ALT was elevated to 2930 IU/l on POD 1, and PGE(1) infusion from SMA was done for the succeeding 7 days. Necrotic area was so vast that serum T. Bil rose to 19 mg/dl. However, it decreased with time. Both cases required 3 months for necrotic liver shrinkage. Doppler ultrasonography revealed that PGE(1) infusion actually increased portal blood flow. In conclusion, based on the preceding experimental backgrounds and clinical experiences, continuous PGE(1) infusion via the SMA can be a useful measure to prevent severe liver damage after hepatic arterial flow interruption through portal blood oxygenation.
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PMID:Two cases of hepatic artery interruption after hepatopancreatobiliary surgery treated by prostaglandin E(1) infusion via the superior mesenteric artery. 1264 44

The efficacy of a low dose of PGE(1)-use on the postoperative liver damage was evaluated. PGE(1) was infused in with the mean rate of 0.026 microg.kg(-1).min(-1) during surgical procedure to 93 patients under GO-enflurane anesthesia (the PG). Serum GOT, GPT and total bilirubin (TBIL) values measured before, at the end of (End) and 3 days (3d) after the operation were compared to those obtained from 43 patients without PGE(1) administration (the control). This dose of PGE(1) did not change blood pressure and heart rate, but slightly decreased Pa(O)(2). In patients with preoperative normal values of GOT, GPT and TBIL, increases in GOT, GPT and TBIL observed at End in the PG were significantly lower than those in the control (31.9 vs 72.2 IU, 25.9 vs 61.9 IU, 0.68 vs 0.83 mg.dl(-1), respectively). GOT, GPT and TBIL at 3d significantly increased in both groups, and these levels were identical between the two groups. In patients with preoperative abnormal values, only GOT at End increased in both groups, while no significant difference between the PG and the control group was noted. GOT at 3d and GPT at End and 3d did not significantly changed in either group. These results suggest that the low dose of PGE(1) administered during an operation prevents the development of postoperative liver damage, but does not treat the damaged hepatic cells.
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PMID:Preventative effect of PGE1 for postoperative liver damage. 1527 56

Prostaglandin E(2) (PGE(2)) mediates a variety of both innate and adaptive immunity responses through 4 distinct receptors, EP1-4. Recent studies have suggested the physiological and pathological role of EP4 in various inflammatory diseases. In this study, we investigated the importance of the EP4 receptor, and the efficacy of a selective EP4 agonist to alter hepatic ischemia/reperfusion (I/R) injury, an important cause of damage in liver resection and transplantation. We used an established murine I/R injury model, 70% partial hepatic ischemia for 90 minutes in male C57BL/6 mice. The local expression of EP4 messenger RNA (mRNA) in the naive and the ischemic liver at 2 hours after reperfusion was examined using RT-PCR analysis. Some mice received the EP4 selective agonist during I/R. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured as markers of hepatic injury. EP4 expression in the liver was significantly up-regulated at 2 hours after reperfusion. Furthermore, treatment with EP4 agonist significantly inhibited hepatic injury at 6 hours after reperfusion. Our data suggest an inhibitory role of EP4 PGE(2) receptor in hepatic I/R injury and the therapeutic efficacy of a selective EP4 agonist for liver protection.
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PMID:Role of EP4 prostaglandin E2 receptor in the ischemic liver. 1580 64

In the present study, latex of Calotropis procera possessing potent antioxidant and anti-inflammatory properties was evaluated for its hepatoprotective effect against carbon tetrachloride (CCl(4)) induced hepatotoxicity in rats. Subcutaneous injection of CCl(4,) administered twice a week, produced a marked elevation in the serum levels of aspartate transaminase (AST), alanine transaminase (ALT) and tumor necrosis factor alpha (TNF-alpha). Histological analysis of the liver of these rats revealed marked necro-inflammatory changes that were associated with increase in the levels of TBARS, PGE(2) and catalase and decrease in the levels of glutathione (GSH), superoxide dismutase (SOD) and glutathione peroxidase (GPx). Daily oral administration of aqueous suspension of dried latex (DL) of Calotropis procera at 5, 50 and 100mg/kg doses produced a dose-dependent reduction in the serum levels of liver enzymes and inflammatory mediators and attenuated the necro-inflammatory changes in the liver. The DL treatment also normalized various biochemical parameters of oxidative stress. Our study shows that the antioxidant and anti-inflammatory effects of DL and silymarin were comparable and suggests that DL could be used as a hepatoprotective agent.
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PMID:Calotropis procera latex affords protection against carbon tetrachloride induced hepatotoxicity in rats. 1770 84

GYY4137 (morpholin-4-ium-4-methoxyphenyl(morpholino) phosphinodithioate) is a slow-releasing hydrogen sulfide (H(2)S) donor. Administration of GYY4137 (50 mg/kg, iv) to anesthetized rats 10 min after lipopolysaccharide (LPS; 4 mg/kg, iv) decreased the slowly developing hypotension. GYY4137 inhibited LPS-induced TNF-alpha production in rat blood and reduced the LPS-evoked rise in NF-kappaB activation, inducible nitric oxide synthase/cyclooxygenase-2 expression, and generation of PGE(2) and nitrate/nitrite in RAW 264.7 macrophages. GYY4137 (50 mg/kg, ip) administered to conscious rats 1 or 2 h after (but not 1 h before) LPS decreased the subsequent (4 h) rise in plasma proinflammatory cytokines (TNF-alpha, IL-1beta, IL-6), nitrite/nitrate, C-reactive protein, and L-selectin. GYY4137 administration also decreased the LPS-evoked increase in lung myeloperoxidase activity, increased plasma concentration of the anti-inflammatory cytokine IL-10, and decreased tissue damage as determined histologically and by measurement of plasma creatinine and alanine aminotransferase activity. Time-expired GYY4137 (50 mg/kg, ip) did not affect the LPS-induced rise in plasma TNF-alpha or lung myeloperoxidase activity. GYY4137 also decreased the LPS-mediated upregulation of liver transcription factors (NF-kappaB and STAT-3). These results suggest an anti-inflammatory effect of GYY4137. The possibility that GYY4137 and other slow-releasing H(2)S donors exert anti-inflammatory activity in other models of inflammation and in humans warrants further study.
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PMID:GYY4137, a novel hydrogen sulfide-releasing molecule, protects against endotoxic shock in the rat. 1937 98


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