Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.6.1.1 (aspartate aminotransferase)
21,665 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Impairment of various functions of the liver and concomitantly increased levels of parameters of liver damage, a clinical entity termed liver failure, is commonly seen after partial hepatectomy. We investigated in a rat model whether damage of the remnant liver was due to local inflammatory responses, and related to endotoxin or interleukin-1 (IL-1). To address this question, the effects of partial hepatectomy on infiltration of immunocompetent cells and expression of major histocompatibility complex (MHC) class II antigen of macrophages in the remnant liver was studied using immunohistochemical techniques. Specific intervention with recombinant N-terminal bactericidal/permeability-increasing protein (rBPI23) to neutralize endotoxin and with IL-1 receptor antagonist (IL-1ra) to block IL-1 activity was used to examine the respective roles of endotoxin and IL-1. After partial hepatectomy, we found an influx of neutrophils, an increased expression of MHC class II antigens, and morphologic changes of Kupffer cells consistent with activation. These inflammatory events coincided with increased serum levels of markers of liver damage (aspartate aminotransferase, alanine aminotransferase, ammonia). Both neutralization of endotoxin and blocking of IL-1 activity reduced hepatic inflammation and reduced serum levels of aminotransferases and ammonia. In addition, liver cell proliferation as assessed by staining for proliferating cell nuclear antigen (PCNA) expression was significantly enhanced when either endotoxin or IL-1 effects were blocked. Thus, our results suggest that local hepatic inflammatory responses inhibit liver cell proliferation and promote liver failure, presumably by affecting the functional capacity of the remnant liver.
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PMID:Endotoxin and interleukin-1 related hepatic inflammatory response promotes liver failure after partial hepatectomy. 759 Jun 69

Acetaminophen (APAP) is a widely used analgesic and antipyretic drug that causes massive centrilobular hepatic necrosis at high doses, leading to death. The objectives of this study were to test our working hypothesis that preplaced cell division and hepatic tissue repair by prior thioacetamide (TA) administration provides protection against APAP-induced lethality and to investigate the underlying mechanism. Male Sprague-Dawley rats were treated with a low dose of TA (50 mg/kg, intraperitoneally [i.p.]) before challenge with a 90% lethal dose (1,800 mg/kg, i.p.) of APAP. This protocol resulted in a 100% protection against the lethal effect of APAP. Because TA caused a 23% decrease of hepatic microsomal cytochromes P-450, the possibility that TA protection may be caused by decreased bioactivation of APAP was examined. A 30% decrease in cytochromes P-450 induced by cobalt chloride failed to provide protection against APAP lethality. Time course of serum enzyme elevations (alanine aminotransferase, aspartate aminotransferase, and sorbitol dehydrogenase) indicated that actual infliction of liver injury by APAP peaked between 12 to 24 hours after the administration of APAP, whereas the ultimate outcome of that injury depended on the biological events thereafter. Although liver injury progressed in rats receiving only APAP, it regressed in rats pretreated with TA. Acetaminophen t1/2 was not altered in TA-treated rats, indicating that significant changes in APAP disposition and bioactivation are unlikely. Moreover, hepatic glutathione was decreased to a similar extent regardless of TA pretreatment, suggesting that decreased bioactivation of APAP is unlikely to be the mechanism underlying TA protection. [3H]Thymidine incorporation studies confirmed the expected stimulation of S-phase synthesis, and proliferating cell nuclear antigen studies showed a corresponding stimulation of cell division through accelerated cell cycle progression. Intervention with TA-induced cell division by colchicine antimitosis ended the TA protection in the absence of significant changes in the time course of serum enzyme elevations during the inflictive phase of APAP hepatotoxicity. These studies suggest that hepatocyte division and tissue repair induced by TA facilitate sustained hepatic tissue repair after subsequent APAP-induced liver injury, producing recovery from liver injury and protection against APAP lethality.
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PMID:Stimulated hepatic tissue repair underlies heteroprotection by thioacetamide against acetaminophen-induced lethality. 784 22

Clinical applications of Type I interferon (IFN) are limited by adverse side effects mediated largely by unknown mechanisms. This study examined the mechanisms of acute hepatic injury in lambs treated with systemic administration of IFN-tau, a Type I IFN. Liver tissues were collected at 24, 48, or 96 hours after treatment with either IFN-tau or saline. Histopathology revealed acute hepatopathy including cellular swelling, cytoplasmic aggregates, and apoptosis in all IFN-tau-treated lambs, which were accompanied by elevation of aspartate transaminase (AST) (P <.01). The number of apoptotic hepatocytes in IFN-tau-treated lambs was higher than for control lambs (P <.001). Immunohistochemistry for proliferating cell nuclear antigen (PCNA) revealed that IFN-tau induced hepatocyte growth arrest at the G0/G1 phase of the cell cycle and that the majority of hepatocytes in S or G2 phase were eliminated by apoptosis. We investigated expression of bax-alpha and bcl-2, acting as pro- and antiapoptotic molecules, in IFN-tau-induced apoptosis. Northern blot analysis revealed increased expression of bax-alpha messenger RNA (mRNA) in IFN-tau-treated lambs (P <.01) compared with control lambs, consistent with the expression pattern for bax-alpha protein. However, there was no detectable difference in expression of bcl-2 proteins between control and IFN-tau-treated lambs. The levels of bax-alpha associated with the mitochondria also increased during IFN-tau treatment. Bax-alpha immunostaining showed scattered immunoreactive hepatocytes with morphological hallmarks of apoptosis. These results suggest that IFN-tau induces growth arrest as well as apoptosis by regulating bax-alpha expression. These pathological effects of IFN-tau on sheep liver indicate potential mechanisms of Type 1 IFN-induced hepatotoxicity in animals and humans.
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PMID:Interferon tau-induced hepatocyte apoptosis in sheep. 1082 53

Recent studies have shown that expression levels of the multidrug resistance gene MDR1, which encodes the drug transporter P-glycoprotein, correlate with prognostic outcomes of certain tumor types. These findings suggest that expression of MDR1 may affect tumor behaviors. To address this issue further, we investigated the expression of mdr1a, a human MDR1 homolog, on the development of hepatocellular carcinoma in a transgenic mouse model carrying the liver-targeted expression of human hepatitis-B virus (HBV) surface antigen. The pathogenetic program was compared in HBV mice carrying either mdr1a(+/+) or mdr1a(-/-). We found that the expressions of proliferative activity markers, Ki67 nuclear antigen, and proliferating cell nuclear antigen were elevated in mdr1a(-/-) mice younger than 10 wk in comparison with those in the same age group of wild-type animals. Replication in the hepatic population as determined by bromodeoxyuridine incorporation tended to support observation that mdr1a(-/-) mice exhibited elevated labeling indices in this age group. Moreover, histologic staining and flow-cytometric analysis showed that the mdr1a(-/-) animals exhibited a higher cell population with polyploidy than did the mdr1a(+/+) counterparts of the same age. However, no significant differences in the expression of the liver-injury markers serum alanine transaminase and aspartate transaminase were observed. Although our results showed that absence of mdr1a expression is correlated with modest enhanced proliferative characteristics in the livers at stage before the development of hepatocellular carcinoma, the overall life spans between these two strains of mice were not significantly different. The implication of these findings to the role of P-glycoprotein in tumor development and cancer chemotherapy is discussed.
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PMID:Elevated expression of hepatic proliferative markers during early hepatocarcinogenesis in hepatitis-B virus transgenic mice lacking mdr1a-encoded P-glycoprotein. 1107 7

Acute liver injury induced by CCl4 injection (0.5 ml/kg b.w.) was compared between Mini and Wistar rats. Mini rats (Jcl:Wistar-TgN (ARGHGEN)1Nts strain) are Wistar-derived transgenic animals in which the expression of growth hormone (GH) gene is suppressed by the presence of an antisense transgene. The hepatic lesion appeared earlier and its recovery was delayed in Mini rats compared to in Wistar rats. The degree of the liver injury was more severe in Mini rats than in Wistar rats, and this corresponded well with the changes in serum AST level. Moreover, in accordance with the localization of CYP2E1-positive hepatocytes in the early stage after CCl4 treatment, the initial lesion characterized by ballooning of hepatocytes developed in the centrilobular zone in Wistar rats while it appeared in the middle zone in Mini rats. The changes in the percentage of PCNA-positive cells and the levels of HGF and TGF-beta1 mRNAs were clearly different between the two strains. These results indicate that the response of the liver to CCl4 is different between GH-suppressed Mini rats and Wistar rats.
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PMID:Carbon tetrachloride-induced acute liver injury in Mini and Wistar rats. 1137 Jul 28

Ischemia reperfusion (I-R) of the liver induces various events leading to cell death (apoptosis) and subsequent cells proliferation. Recent experimental studies have described the protective effect of ischemic preconditioning (IPC) on I-R injury of the liver. However, the mechanisms involved in this protection remain unknown. The protein products of immediate early genes (IEGs) behave as crucial transcriptional regulators not only in apoptosis but also in cell proliferation. Here, we evaluated the effects of IPC on IEG transcription after I-R injury, using a rat liver I-R injury model. Injury to hepatocytes was evaluated by measuring serum levels of aspartate transaminase (AST), alanine transaminase (ALT), and lactate dehydrogenase (LDH) and that to endothelial cells by plasma concentration of hyaluronic acid (HA). The extent of necrosis was evaluated by H&E staining, while cell proliferation and apoptosis were evaluated by proliferating cell nuclear antigen (PCNA) and terminal deoxy(d)-UTP nick end labelling (TUNEL) staining, respectively. Alterations in the transcription of IEGs (c-fos and c-jun) were examined by Northern blotting. Rats subjected to 40-min liver ischemia, preceded by 10-min preconditioning, showed significantly lower AST, ALT, LDH, and HA levels at 6 h after I-R than untreated animals (P < 0.05; n at least 5 rats per group). The percentage of necrotic areas at 24 h after I-R was significantly lower in IPC-treated animals than in the controls. The numbers of apoptotic cells at 24 h after I-R and the numbers of PCNA-positive cells at 24 and 48 h after I-R were significantly lower in IPC-treated rats than in controls. Transcription levels of IEGs were low in IPC-treated rats, particularly c-jun at 1 and 1.5 h after I-R (P < 0.05). Our results indicate that IPC provides a significant protective effect on for liver cells against I-R injury and that its effect is evidenced by a significant decrease in the transcription levels of IEGs following the insult.
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PMID:Effects of preconditioning on ischemia/reperfusion injury of hepatocytes determined by immediate early gene transcription. 1170 57

In order to study sub-acute hepatotoxicity of low doses of microcystins in vivo, as well as to understand the mechanisms of hepatotoxicity of microcystins, eighty Spague-Dawley rats were injected with microcystins intraperitoneally at the doses of 0, 4, 8 and 12 micrograms.(kg.d)-1, respectively, for 35 days. Then blood and liver samples were used for assay. Several enzymatic levels and pathological changes were detected. Both terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) and immunohistochemical methods were employed to study the apoptosis and proliferating cell nuclear antigen (PCNA). It was shown that the activity of serum gamma-glutamyltransferase (GGT) and concentrations of whole blood glutathione (GSH) decreased, serum activities of lactate dehydrogenase (LDH) and aminotransferase (AST) increased after exposure to MC. No significant change of concentration of serum alanine aminotransferase (ALT) was observed in the tested groups. Characteristic morphological alterations and active proliferation as well as apoptosis of hepatotocytes were observed in the treated groups. It was suggested that oxidative injury and apoptosis of hepatocytes induced by microcystins may be the mechanisms of its hepatotoxicity.
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PMID:[Sub-acute hepatotoxicity of low doses of microcystins]. 1253 25

Decalin (decahydronaphthalene) is a widely used industrial solvent known to cause male rat-specific alpha2u-globulin nephropathy. In this project, 13-week and two-year inhalation studies of decalin were conducted consecutively in both sexes of F344/N rats. The key objectives were to (1) characterize the 13-week toxicity of decalin in rats, with an emphasis on nephropathy in males; (2) compare the kidney concentrations of decalin, 2-decalone, and alpha2u-globulin in males over 2 to 13 weeks of decalin exposure; and (3) correlate male rat nephropathy observed in the 13-week study with renal carcinogenicity in the two-year study. F344 rats (M/F) were exposed via whole-body inhalation to 0, 25, 50, 100, 200, or 400 ppm decalin for 13 weeks. Urine was collected at weeks 2 and 6 for creatinine and decalol analyses and at week 12 for clinical urinalysis. Right kidneys were collected from male rats at weeks 2 and 6 and from both sexes at week 13, homogenates were prepared using the whole kidney, and these homogenates were analyzed for alpha2u-globulin, decalin, and 2-decalone. Left kidneys were evaluated for histopathology and cell proliferation utilizing a proliferating cell nuclear antigen technique and counting proximal renal tubular epithelial cells to determine cell labeling indices. Necropsies and histopathologic evaluations were performed at week 13. Decalin exposure caused increases in kidney weight, urinalysis parameters (protein, AST, LDH), kidney alpha2u-globulin concentration, and proximal convoluted renal tubular cell proliferation in males. These changes were accompanied by microscopic lesions (accumulation of hyaline droplets in cortical tubules, regeneration of proximal tubular epithelium, and granular casts in medullary tubules) clearly linked to alpha2u-globulin nephropathy. Both decalin and 2-decalone were related to increased alpha2u-globulin in male kidneys. Kidney concentrations of decalin, 2-decalone, and alpha2u-globulin in exposed females were negligible, while females excreted greater amounts of decalol metabolites in urine than males at weeks 2 and 6. There were no exposure-related microscopic lesions in females. For chronic exposure, F344 rats were exposed via whole-body inhalation to 0, 25, 50 (males only), 100, or 400 ppm decalin for two years. Chronic exposure induced a spectrum of nonneoplastic and neoplastic lesions in the renal cortex of males, ranging from regenerative lesions of chronic nephropathy to tubular carcinomas. Incidences of renal tubular adenoma, tubular carcinoma, combined tubular adenomas and carcinomas, cortical tubular hyperplasia, hyaline droplet accumulation, hyperplasia of pelvic epithelium, and mineralization in renal papilla were increased in exposed males compared to controls. There was a clear increase in the mean severity of chronic nephropathy in decalin-exposed males. It was concluded that the carcinogenic effect on the renal cortical epithelium of male rats exposed to decalin was related to increased turnover of this epithelium, resulting from the cytotoxic effects of alpha2u-globulin accumulation in the renal cortical tubular cell cytoplasm.
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PMID:Alpha 2u-globulin nephropathy and carcinogenicity following exposure to decalin (decahydronaphthalene) in F344/N rats. 1266 Mar 59

Streptozotocin (STZ)-induced diabetic (DB) mice challenged with single ordinarily lethal doses of acetaminophen (APAP), carbon tetrachloride (CCl4), or bromobenzene (BB) were resistant to all three hepatotoxicants. Mechanisms of protection against APAP hepatotoxicity were investigated. Plasma alanine aminotransferase, aspartate aminotransferase, and liver histopathology revealed significantly lower hepatic injury in DB mice after APAP administration. HPLC analysis of plasma and urine revealed lower plasma t1/2, increased volume of distribution (Vd), and increased plasma clearance (CLp) of APAP in the DB mice and no difference in APAP-glucuronide, a major metabolite in mice. Interestingly, covalent binding of 14C-labeled APAP to liver target proteins; arylation of APAP to 58, 56, and 44 kDa acetaminophen binding proteins (ABPs); and glutathione (GSH) depletion in the liver did not differ between nondiabetic (non-DB) and DB mice in spite of downregulated hepatic microsomal CYP2E1 and 1A2 proteins in the DB mice, known to be involved in bioactivation of APAP. Compensatory cell division measured via 3H-thymidine pulse labeling and immunohistochemical staining for proliferating cell nuclear antigen (PCNA) indicated earlier onset of S-phase in the DB mice after exposure to APAP. Antimitotic intervention of liver cell division by colchicine (CLC) after administration of APAP led to significantly higher mortality in the DB mice suggesting a pivotal role of liver cell division and tissue repair in the protection afforded by diabetes. In conclusion, the resistance of DB mice against hepatotoxic and lethal effects of APAP appears to be mediated by a combination of enhanced APAP clearance and robust compensatory tissue repair.
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PMID:Type 1 diabetic mice are protected from acetaminophen hepatotoxicity. 1270 Apr 23

In the present study, the effect of FR167653, a novel suppressive agent against interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), on liver regeneration was investigated in rats after partial hepatectomy (PH). Doses of 1, 3 and 5 mg/kg per h FR167653 (FR-1, FR-3 and FR-5, respectively) were given intravenously 30 min before PH, while the control was given normal saline. Serum chemistries were serially monitored, and liver regeneration was evaluated by remnant liver weight ratio, proliferating cell nuclear antigen (PCNA) labeling index and mitotic index. Accumulation of IL-1beta and TNF-alpha messenger RNA (mRNA) in the remnant liver was also measured. In FR167653-treated groups, the releases of alanine transaminase (ALT) and aspartate transaminase (AST) were lower. The PCNA labeling index was enhanced by FR167653-administration in a dose-dependent manner, FR-3 and FR-5 groups showed significantly higher peak DNA synthesis than the control group at 24 h post-PH (P<0.01). The mitotic index was also enhanced by FR167653-administration in a dose-dependent manner. In FR-5 group, the remnant liver weight ratio was significantly higher than that in the control group (P<0.05). The accumulation of IL-1beta messenger RNA (mRNA) in the remnant liver was obviously suppressed in FR-3 and FR-5 groups, but the expression of TNF-alpha mRNA was not apparently reduced. In conclusion, FR167653 ameliorates liver injury and enhances liver regeneration after PH in rats.
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PMID:A new suppressive agent against interleukin-1beta and tumor necrosis factor-alpha enhances liver regeneration after partial hepatectomy in rats. 1278 3


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