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)

Reductive metabolism of halothane in phenobarbital-pretreated rats is known to increase free radical formation that results in hepatotoxicity. It also is associated with a marked induction of microsomal heme oxygenase-1 (HO-1), suggesting that there is an alteration in heme metabolism. In this study, we examined heme metabolism in rats pretreated with phenobarbital, followed by exposure to halothane-hypoxia. In this model, there was a significant decrease in microsomal cytochrome P450 content in the liver, followed by a rapid increase in free heme concentration and a decrease in the level of mRNA for the nonspecific delta-aminolevulinate synthase. A transient but dramatic induction of HO-1 mRNA and a prolonged induction of heat shock protein 70 mRNA also occurred. The HO-1 protein was detected principally in the hepatocytes around the central vein. Serum alanine transaminase (ALT) activity, an indicator of hepatic dysfunction, increased continuously throughout the experiment. Hemin pretreatment induced hepatic HO-1 with abrogation of the halothane-induced hepatotoxicity in this model, as judged by ALT activity and normal histology. Our findings in this study thus indicate that halothane-induced hepatotoxicity is due not only to its reductive metabolite formation, but also to an increase in hepatic free heme concentration, which is a potent prooxidant; HO-1 induction is an important protective response against such changes. This is also the first study to demonstrate that hemin pretreatment, which induces HO-1 prior to exposure to halothane, effectively prevents halothane-induced hepatotoxicity.
 ...
PMID:Prevention of halothane-induced hepatotoxicity by hemin pretreatment: protective role of heme oxygenase-1 induction. 1071 46

Isoflurane is considered to be a less hepatotoxic volatile anesthetic than halothane since it not only undergoes quantitatively much less metabolism to form toxic reactive intermediates, but also preserves better hepatic blood flow. However, the biochemical basis for the reduced hepatotoxicity has not been elucidated. In this study, we examined the induction of two heat shock proteins, heat shock protein 70 (HSP70) and heme oxygenase-1 (HO-1), in the livers of rats pretreated with or without phenobarbital, followed by exposure to isoflurane or halothane under hypoxic conditions. In the phenobarbital-pretreated rats, the maximal induction of HSP70 was observed by halothane-hypoxia treatment, followed by a half-maximal induction by isoflurane-hypoxia treatment, and less than 30% induction by hypoxia treatment alone. Serum alanine aminotransferase (ALT) activity, an indicator of hepatic dysfunction, which correlated well with the extent of centrilobular necrosis, showed similar changes with increases in HSP70 mRNA. In contrast, HO-1 mRNA was induced only by treatment with halothane-hypoxia. In addition, changes in the expression of HSP70 and HO-1 mRNAs were correlated with their protein expression in the liver. In non-pretreated rats, neither isoflurane-hypoxia exposure nor halothane-hypoxia exposure caused apparent hepatic injury. There was also no induction of HSP70 or HO-1 mRNA by these treatments in non-pretreated animals. These findings demonstrate that there is a significant difference in hepatic injury, and in the induction of HO-1 and HSP70 between halothane-hypoxia and isoflurane-hypoxia treatments. Isoflurane is known to be safer than halothane, which may, in part, be accounted for by the generation of less oxidative stress in the presence of isoflurane, as assessed by reduced induction of heat shock proteins compared with halothane treatment.
 ...
PMID:Differential effects of isoflurane and halothane on the induction of heat shock proteins. 1143 12

Hyperthermic preconditioning attenuates the heat-induced cellular response to a subsequent severe heat challenge. However, it is impractical to perform whole-body hyperthermia in humans. This study was designed to test the hypotheses that hepatic heat shock protein 70 (Hsp70) could be induced by local somatothermal stimulation (LSTS) on right seventh intercostal nerve territory and that preconditioning the rats with LSTS protects the liver from subsequent ischemia-reperfusion injury. LSTS was brought about by application of a heating rod above right seventh intercostal nerve territory in male Sprague-Dawley rats. Hepatic gene expression of Hsp70 was assessed by Western blot and reverse transcription polymerase chain reaction (RT-PCR). Finally, serum ALT and AST and the lipid peroxidation product malondialdehyde (MDA) were evaluated in ischemic-reperfused rats preconditioned by application of LSTS on right seventh intercostal nerve territory. The results showed that hepatic gene expression of Hsp70 was upregulated in rats treated with LSTS. When animals were preconditioned with LSTS, followed by subsequent ischemia-reperfusion injury of the liver, there were significant decreases in liver enzymes (ALT/AST) and MDA formation in rats pretreated with one dose of LSTS (LSTS-1 group) as compared with those not treated with LSTS (control group) or treated with three doses of LSTS (LSTS-3 group). We conclude that mild local heat stress (one dose) on right seventh intercostal nerve territory upregulates hepatic gene expression of Hsp70 and protects the liver from subsequent ischemia-reperfusion injury. This might provide an easily applicable method for those patients facing ischemia-reperfusion challenge of the liver, as in liver resection and liver transplantation.
 ...
PMID:Preconditioning somatothermal stimulation on right seventh intercostal nerve territory increases hepatic heat shock protein 70 and protects the liver from ischemia-reperfusion injury in rats. 1146 6

Overproduction of heat shock protein 70 (HSP70) in the liver protects hepatocytes under various pathologic conditions. In this study we examined the effects of a nontoxic HSP70 inducer, geranylgeranylacetone (GGA), on acute hepatic failure after 95% hepatectomy in rats. When GGA (100 mg/kg) or vehicle was intragastrically administered to rats 4 hours before 95% hepatectomy, all 25 rats pretreated with vehicle died within 60 hours after the operation, whereas 10 of 25 rats pretreated with GGA survived. During the 24-hour postoperative period, GGA significantly suppressed the release of aspartate or alanine aminotransferase and elevation of the serum interleukin-6 level, and completely inhibited an increase in the serum level of tumor necrosis factor-alpha. Histologic examinations showed that GGA prevented hemorrhagic necrosis, which was observed in vehicle-treated livers more than 12 hours after the operation. During the 24-hour postoperative period, HSP70 induction was absent in remnant livers of vehicle-treated rats. In contrast, GGA stimulated the HSP70 mRNA expression and HSP70 accumulation within 4 hours, and viable hepatocytes contained abundant HSP70 in their nuclei. Our results suggest that GGA may prevent acute liver failure after massive hepatectomy, at least in part, by enhancing HSP70 induction in the remnant liver.
 ...
PMID:Geranylgeranylacetone suppresses inflammatory responses and improves survival after massive hepatectomy in rats. 1202 1

The chronic hepatotoxic effects of carbon tetrachloride (CCl(4)) in heat-shock protein (HSP) 70 knock out (HSP70-/-) mice were examined. After repeated intraperitoneal injections of CCl(4) for six weeks, the level of ALT and weight ratio of the liver to body were lower in HSP70-/- mice than in the control (WT) mice. The levels of HSP25 and HSP47 were lowered in HSP70-/- mice as compared with WT mice. The grades of hepatic necrosis and neutrophil infiltration were not significantly different between HSP70-/- and WT mice. The collagen content was not affected significantly by CCl(4) treatment.
 ...
PMID:Chronic hepatotoxicity of carbon tetrachloride in hsp-70 knock out mice. 1499 37

Glutaredoxins (Grxs) are small ubiquitous proteins of the thioredoxin (Trx) family, which catalyze dithiol-disulfide exchange reactions or reduce protein-mixed glutathione disulfides. In plants, several Trx-interacting proteins have been isolated from different compartments, whereas very few Grx-interacting proteins are known. We describe here the determination of Grx target proteins using a mutated poplar Grx, various tissular and subcellular plant extracts, and liquid chromatography coupled to tandem mass spectrometry detection. We have identified 94 putative targets, involved in many processes, including oxidative stress response [peroxiredoxins (Prxs), ascorbate peroxidase, catalase], nitrogen, sulfur, and carbon metabolisms (methionine synthase, alanine aminotransferase, phosphoglycerate kinase), translation (elongation factors E and Tu), or protein folding (heat shock protein 70). Some of these proteins were previously found to interact with Trx or to be glutathiolated in other organisms, but others could be more specific partners of Grx. To substantiate further these data, Grx was shown to support catalysis of the stroma beta-type carbonic anhydrase and Prx IIF of Arabidopsis thaliana, but not of poplar 2-Cys Prx. Overall, these data suggest that the interaction could occur randomly either with exposed cysteinyl disulfide bonds formed within or between target proteins or with mixed disulfides between a protein thiol and glutathione.
 ...
PMID:Identification of plant glutaredoxin targets. 1599 47

The impact of 3 different reperfusion sequences following orthotopic liver transplantation (OLT) in pigs were evaluated. The reperfusion technique commonly performed is primary portal in order to shorten warm ischemic times (WITs). Experimental and clinical data, usually comparing 2 out of 3 possible reperfusion sequences, provide controversial results. OLT was performed in 24 pigs randomized into 3 groups: primary arterial (A), simultaneous (SIM), and primary portal (P) reperfusion. Hemodynamics were continuously monitored and reperfusion injury and primary graft function were assessed by standard serum parameters, histopathological findings, immunohistochemistry for heme oxygenase 1 (HO-1), and heat shock protein 70 (HSP 70). Aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), and gamma-glutamyl transpeptidase (gammaGT) following reperfusion were significantly increased for group A when compared to groups SIM and P. Hemodynamics showed significant differences after reperfusion compared to physiological data; differences in group comparisons were not significant. The bile production/100 g liver/hr was significantly higher for group SIM (1.15 mL) compared to group P (0.66 mL) and group A (0.62 mL). Histology and immunohistochemistry significantly correlated with functional results and outcome. Histological score was best for group SIM and worst for group A. HSP 70, being visualized mainly in the hepatocytes, showed higher expression for groups SIM and P. Inversely, HO-1, found in perisinusoidal cells, showed highest expression after primary arterial reperfusion. In conclusion, although associated with a 10-minute longer warm ischemic time, simultaneous reperfusion causes the least reperfusion injury with superior primary transplant function. Primary arterial reperfusion showed the worst overall outcome and highest degree of HO-1 expression.
 ...
PMID:Sequence of reperfusion influences ischemia/reperfusion injury and primary graft function following porcine liver transplantation. 1618 69

The current study explored the concept that adult and pediatric populations differ in their response to major injury. Male C57BL/6 mice of a "young adult" (8-12 weeks) or "mature adult" (12-13 months) age were subjected to partial hepatic ischemia and reperfusion. Mature adult mice displayed significantly more liver injury than young adult mice as assessed histologically and by serum levels of alanine aminotransferase. Interestingly, there was far less neutrophil accumulation in the livers of mature adult mice. However, liver-recruited neutrophils from mature adult mice had a higher activation state than those from young adult mice. Activation of the inflammatory transcription factor, NF-kappaB, was suppressed in whole livers from mature adult mice. In isolated liver cells, Kupffer cells showed no difference in NF-kappaB activation, but hepatocytes from mature adult mice had delayed NF-kappaB activation in response to TNF. Furthermore, isolated hepatocytes from young adult mice produced abundant amounts of the chemokine, macrophage inflammatory protein-2, whereas hepatocytes from mature adult mice produced little, if any macrophage inflammatory protein-2. Mature adult mice had much lower hepatic expression of the cytoprotective protein, heat shock protein 70, than did young adult mice. In contrast, serum heat shock protein 70 levels, which has been linked to subsequent tissue injury, were higher in mature adult mice than in young adult mice. These data suggest that there are multiple alterations at the cellular and molecular levels that contribute to enhanced postischemic liver injury in mature adult mice.
 ...
PMID:Age-dependent responses to hepatic ischemia/reperfusion injury. 1624 27

Although studies indicate that 17beta-estradiol administration after trauma-hemorrhage (T-H) improves cardiac and hepatic functions, the underlying mechanisms remain unclear. Because the induction of heat shock proteins (HSPs) can protect cardiac and hepatic functions, we hypothesized that these proteins contribute to the salutary effects of estradiol after T-H. To test this hypothesis, male Sprague-Dawley rats ( approximately 300 g) underwent laparotomy and hemorrhagic shock (35-40 mmHg for approximately 90 min) followed by resuscitation with four times the shed blood volume in the form of Ringer lactate. 17beta-estradiol (1 mg/kg body wt) was administered at the end of the resuscitation. Five hours after T-H and resuscitation there was a significant decrease in cardiac output, positive and negative maximal rate of left ventricular pressure. Liver function as determined by bile production and indocyanine green clearance was also compromised after T-H and resuscitation. This was accompanied by an increase in plasma alanine aminotransferase (ALT) levels and liver perfusate lactic dehydrogenase levels. Furthermore, circulating levels of TNF-alpha, IL-6, and IL-10 were also increased. In addition to decreased cardiac and hepatic function, there was an increase in cardiac HSP32 expression and a reduction in HSP60 expression after T-H. In the liver, HSP32 and HSP70 were increased after T-H. There was no change in heart HSP70 and liver HSP60 after T-H and resuscitation. Estradiol administration at the end of T-H and resuscitation increased heart/liver HSPs expression, ameliorated the impairment of heart/liver functions, and significantly prevented the increase in plasma levels of ALT, TNF-alpha, and IL-6. The ability of estradiol to induce HSPs expression in the heart and the liver suggests that HSPs, in part, mediate the salutary effects of 17beta-estradiol on organ functions after T-H.
 ...
PMID:Estradiol improves cardiac and hepatic function after trauma-hemorrhage: role of enhanced heat shock protein expression. 1625 24

The administration of glutamine before experimental ischemia/reperfusion (I/R) has been shown to protect intestinal, pulmonary, and myocardial tissue by inducing heat shock proteins (HSP). However, it is not known whether glutamine is protective for all organs. We therefore tested whether pretreatment with glutamine reduces injury following hepatic I/R in rats. Male lean Zucker rats were pretreated with either glutamine (0.75 g/kg intraperitoneally, n = 6) or saline (n = 6), 24 and 6 hours before ischemia. Seventy percent of the liver was exposed to 75 minutes of warm ischemia followed by 24 hours reperfusion. Liver enzymes, histology, neutrophil accumulation, survival, and heat shock protein (HSP) 70 induction were examined. Glutamine administration did not reduce liver injury. In both groups, 5 of 6 animals survived 24 hours of reperfusion. There was no difference in serum transaminase levels with AST 15113 +/- 4336 U/L (glutamine) vs. 17695 +/- 8531 U/L (control, P > 0.05), and ALT 7763 +/- 2524 (glutamine) U/L vs. 5884 +/- 2063 U/L (control, P > 0.05). The degree of neutrophil accumulation and necrosis was not different between groups at 24 hours of reperfusion. Pretreatment did not result in HSP70 upregulation in any of the groups. Pretreatment with glutamine did not reduce hepatic ischemia/reperfusion injury. The lack of protection was associated with an absence of HSP70 upregulation prior to ischemia.
 ...
PMID:Glutamine does not protect against hepatic warm ischemia/reperfusion injury in rats. 1645 56


1 2 3 4 5 6 7 8 9 Next >>