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

We have compared the effects of BW755C, a dual inhibitor of the arachidonic acid cyclo-oxygenase and lipoxygenase, with the effects of colchicine and indomethacin on the reversion of the biochemical and histochemical signs of rat liver cirrhosis. This was induced by i.p. administration of CCl4 for 11 weeks. At this point the rats were divided into four groups (10 animals each). CCl4 administration was continued for one month along with either colchicine, BW755C or indomethacin. No additional treatment was given to the control group. BW755C consistently improved all the parameters studied. Although colchicine also improved all but two markers (serum ALT activity and serum proteins) it ranked lower than BW755C in most of them. Indomethacin only modified favourably serum alkaline phosphatase activity, serum proteins, cholesterol and bilirubins and liver collagen content. The effects of BW755C could be mainly attributed to the inhibition of the lipoxygenase pathway. A common feature of colchicine, adrenal steroids and BW755C was the ability to inhibit the formation of leukotriene and other lipoxygenase products. The possibility that this property might contribute to their anti-cirrhotic actions is discussed.
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PMID:Reduction of apparent indicators of liver cirrhosis in rats by the arachidonate lipoxygenase inhibitor BW755C. 288 11

The role of leukotrienes was investigated in frog virus 3-induced hepatitis in rats. Frog virus 3 elicited an enhanced generation of cysteinyl leukotrienes in vivo as monitored by measurement of N-acetyl-leukotriene E4 as the major endogenous metabolite of cysteinyl leukotrienes secreted into rat bile. N-Acetyl-leukotriene E4 concentrations were elevated for more than 4 hr after frog virus 3 injection. In vitro experiments using cultured rat liver Kupffer cells of high purity indicated that these cells can produce and metabolize leukotrienes and are thus a possible source of leukotrienes elicited in vivo by frog virus 3. The selective 5-lipoxygenase inhibitor AA 861 and the dual inhibitor of arachidonate lipoxygenase and cyclooxygenase, BW 755C, reduced the hepatocellular injury after a high dose of frog virus 3 by about 50 and 80%, respectively, as judged from plasma activities of ALT and sorbitol dehydrogenase at 24 hr after frog virus 3 administration. Our in vivo and in vitro studies argue in favor of an important role of leukotrienes as mediators in frog virus 3 hepatitis in rats.
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PMID:Leukotrienes as mediators in frog virus 3-induced hepatitis in rats. 311 68

In vitro techniques make a major contribution to the development of alternatives to the in vivo "Draize" skin irritation test, and the development of sensitive and generally applicable in vitro endpoints of cutaneous toxicity is an area of intensive research. To investigate in vitro characteristics of cutaneous irritation, skin explants of rabbit and human origin were topically exposed to chemical irritants, after which the culture medium was analyzed for the presence of metabolites of both arachidonic and linoleic acid. In rabbits exposed to the potent irritant benzalkonium chloride, a direct relation was established between clinical signs of irritation and in vitro release of the proinflammatory mediator 12-hydroxyeicosatetraenoic acid (12-HETE) by the exposed skin. Histological examination revealed varying degrees of epidermal damage. 12-HETE was also the predominant hydroxy fatty acid released in a dose-dependent way by rabbit skin cultures after in vitro exposure to sodium dodecyl sulfate (SDS), benzalkonium chloride (BC), and formaldehyde (FA). Human skin cultures released, in addition to 12-HETE, predominantly 15-HETE and 13-hydroxyoctadecadienoic acid (13-HODE), omega-6 oxygenase products of arachidonic acid and linoleic acid, respectively. The irritant-induced release of hydroxy fatty acids was strongly inhibited by the lipoxygenase inhibitor eicosatetraynoic acid, indicating enzyme-mediated generation of these bioactive lipids. Comparison of hydroxy fatty acid release to more established markers of cytotoxicity (leakage of the cellular enzymes, such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH)) revealed that increased levels of 13-HODE, 9-HODE, 12-HETE, and ALT were specific markers of cutaneous irritancy in rabbit skin cultures.
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PMID:Release of arachidonic and linoleic acid metabolites in skin organ cultures as characteristics of in vitro skin irritancy. 760 24

We employed a bile duct ligation (BDL) model of cholestatic liver injury to test the hypothesis that this form of preexisting hepatic dysfunction alters the kinetics of circulating TNF-alpha and IL-6 after Escherichia coli endotoxemia, thereby augmenting mortality and lung injury by a TNF-alpha:leukotriene (LT) axis of inflammation. Male rats were catheterized 13 d after BDL or sham surgery and studied while awake 18 to 24 h later. Cholestasis after BDL was confirmed by baseline serum bilirubin (BDL = 7.34 +/- 0.72 mg/dl, mean +/- SEM, n = 17 versus Sham = 0.25 +/- 0.07, n = 20; p < 0.005) and histopathology. Sham and BDL animals received E. coli lipopolysaccharide serotype O55:B5 (LPS, 5 mg/kg i.v.) or 0.9% NaCl (NS) ending at t = 0 and were monitored over 24 h for vital signs and hemodynamics. In parallel studies, lipoxygenase inhibition was performed using diethylcarbamazine or the 5-lipoxygenase activating-protein inhibitor MK-886. Blood was collected at baseline and at t = 1.5, 3.5, and 24 h for formed elements and for serum endotoxin, TNF-alpha, IL-6, bilirubin, and alanine aminotransferase (ALT). Organs were evaluated at 24 h for histopathology, including neutrophil (PMN) densities and wet/dry weight (W/D) ratios. Cholestasis reduced survival after otherwise nonlethal endotoxemia, with seven of 11 BDL + LPS rats dying within 24 h versus no deaths in BDL + NS (n = 6), Sham + LPS (n = 14), or Sham + NS (n = 6) animals (p < 0.01). Despite equivalent serum endotoxin between groups, circulating TNF-alpha was 8-fold higher in BDL + LPS than in Sham + LPS rats at 1.5 and 3.5 h (p < 0.001), whereas serum TNF-alpha did not differ between BDL + NS and Sham + NS rats. IL-6 likewise was increased differentially by 1.5 h in BDL + LPS animals (11.98 +/- 2.42 ng/ml) versus Sham + LPS rats (3.05 +/- 0.58 ng/ml, p < 0.05). Hypothermia, bradycardic hypotension, and leukopenia were most severe and prolonged in BDL + LPS rats, which also had significantly higher ALT values, W/D ratios, and organ PMN counts. LT inhibition failed to reduce BDL-related differences in serum cytokines or survival after endotoxemia. Thus, cholestasis augments inflammatory responses to gram-negative endotoxemia, sensitizing the host to enhanced fluid flux in multiple organs and to mortality by a LT-independent mechanism.
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PMID:Cholestatic liver injury increases circulating TNF-alpha and IL-6 and mortality after Escherichia coli endotoxemia. 960 37

In order to study the contribution of eicosanoids to the regulation of the functions of normal and carbon tetrachloride (CCl4)-injured liver cells, primary cultures of hepatocytes (HC) either alone or in coculture with Kupffer cells (KC) were exposed for 4 and 24 h to lipoxygenase inhibitor (nordihydroguaiaretic acid-NDGA) or cyclooxygenase inhibitor (indomethacin-IND) in the presence and in the absence of CCl4. Treatment with CCl4 resulted in increased ALT release and a decreased mitochondrial respiration (MR) in HC and their cocultures with KC. The addition of NDGA decreased ALT levels and increased MR in control and CCL4-injured cells. Urea production (UP) was not significantly affected by NDGA. In contrast, addition of IND) decreased UP by HC (4 h), and did not alter ALT release and MR in control and CCl4-treated cells. These results indicate that arachidonic acid metabolites are involved in the regulation of HC flinctions. There is also evidence that a protective action of lipoxygenase inhibitors on CCl4-injured liver is mediated, at least partly, by their direct effects on HC and KC, in particular by increasing the mitochondrial respiration.
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PMID:Effects of nordihydroguaiaretic acid and indomethacin on the viability and functional activities of normal and carbon tetrachioride-injured rat hepatocytes cultured alone and with Kupffer cells. 1034 18

Leukotrienes (LTs) are thought to be extensively involved in a liver damage in vivo through different mechanisms. In this study we used different doses (10(-7)-10(-12) M) of the dehydroxilated LTB4 and the cysteinyl LTC4 to estimate their direct injurious effects on cultured rat hepatocytes (HC). Our experiments demonstrated that exogenous LTB4 and LTC4 caused a rapid and transient increase in alanine aminotransferase release from HC and a slight, but significant decrease of mitochondrial electron transport chain activity in HC. Significant increases in ALT release were observed with LTs doses as low as 10(-12) M, but the loss of mitochondrial function was significant only at the two higher doses (10(-7) and 10(-8) M). HC were treated with the lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA) to inhibit the possible synthesis of endogenous LTs. The effects of exogenous LTB4 and LTC4 on NDGA-treated HC tended to be similar to those indicated in the absence of inhibitor, but were more pronounced. These data suggest that LTs may be involved in the direct damage of liver cells under pathological conditions associated with enhanced LTs formation.
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PMID:Effects of exogenous leukotrienes B4 and C4 on the viability of cultured rat hepatocytes. 1168 52

Increasing evidence regarding free-radical generating agents and the inflammatory process suggests that accumulation of reactive oxygen species (ROS) can involve hepatotoxicity. Previously, we found that protocatechuic acid (PCA), a polyphenolic compound from Hibiscus sabdariffa L. possessing free radical-scavenging capacity, protected against oxidative damage induced by tert-butylhydroperoxide (t-BHP) in rat primary hepatocytes. In this study, first PCA was evaluated by its capacity of inhibiting xanthine oxidase (XO) and lipoxygenase (LO) activity in vitro, then it was used to induce hepatotoxicity to assess the antioxidant and anti-inflammatory bioactivity of PCA in vivo. Our investigation showed that pretreatment with PCA (50-100 mg/kg) by gavage for 5 days before a single dose of t-BHP (ip; 0.2 mmol/kg ) significantly lowered serum levels of the hepatic enzyme markers lactate dehydrogenase (LDH) and alanine (ALT) and aspartate (AST) aminotransferase, and reduced oxidative stress of the liver by evaluating malondialdehyde (MDA) and glutathione (GSH). Histopathological evaluation of the rat livers revealed that PCA reduced the incidence of liver lesions, including hepatocyte swelling, leukocyte infiltration, and necrosis induced by t-BHP. In addition, PCA inhibited t-BHP-induced tyrosine phosphorylation, an implication of the activation of a stress signal pathway, in the liver. These results indicate that PCA protects against t-BHP-induced hepatotoxicity by its antioxidant and anti-inflammatory characteristics accompanied by blocking of stress signal transduction.
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PMID:In vivo protective effect of protocatechuic acid on tert-butyl hydroperoxide-induced rat hepatotoxicity. 1195 69

Arachidonic acid metabolites have been shown to have a wide range of effects on cell proliferation and viability. In this study, the effects of lipoxygenase (LO) inhibitors nordihydroguaiaretic acid (NDGA) and caffeic acid (CA) on the viability of cultured rat hepatocytes (HC) were investigated. As a result, treatment with NDGA and CA for 4 h and 24 h decreased ALT release from HC and increased a number of apoptotic cells. Apoptosis inducing effects of general LO inhibitor NDGA were more pronounced, than those of 5-LO inhibitor CA. The results suggest that lipoxygenase pathway of arachidonic acid metabolism, in particular 5-LO, is essential regulator of hepatocyte survival and apoptosis.
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PMID:[Lipoxygenase inhibitors induce rat hepatocyte apoptosis in primary culture]. 1219 93

The beneficial influence of dietary curcumin, capsaicin and their combination on the susceptibility of low-density lipoprotein (LDL) to oxidation was examined in an animal study. Individually, both dietary curcumin and capsaicin significantly inhibited the in vivo iron-induced LDL oxidation, as well as copper-induced oxidation of LDL in vitro. The protective effect of the combination of curcumin and capsaicin on LDL oxidation was greater than that of individual compounds. This protective influence of spice principles was also indicated by the relative anodic electrophoretic mobility of oxidized LDL on agarose gel. In another study, rats injected with iron showed hepatic toxicity as measured by an increase in lipid peroxides and elevated serum enzymes, alanine aminotransferase, aspartate aminotransferase and lactate dehydrogenase. Dietary curcumin, capsaicin and their combination reduced the activities of these enzymes, and lowered the liver lipid peroxide level, indicating amelioration of the severity of iron-induced hepatotoxicity. In yet another study, a comparison of the extent of carrageenan-induced paw inflammation showed that both dietary curcumin and capsaicin moderately lowered inflammation, while the spice principles in combination were more effective. Dietary curcumin and capsaicin significantly decreased the activity of 5'-lipoxygenase activity in the polymorphonuclear lymphocytes in carrageenan-injected rats, the decrease being even higher in the case of combination of these two spice principles. Results suggest that dietary curcumin and capsaicin individually are protective to LDL oxidation both in vivo and in vitro, to iron-induced hepatotoxicity and to carrageenan-induced inflammation. This beneficial effect was higher when the two compounds were fed in combination.
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PMID:Protective effect of dietary curcumin and capsaicin on induced oxidation of low-density lipoprotein, iron-induced hepatotoxicity and carrageenan-induced inflammation in experimental rats. 1695 63

Five-lipoxygenase (5-LO) has been postulated as a pathogenic factor in liver injury. Indeed, Alox5, the gene coding for 5-LO, is heavily over-expressed in experimental liver disease, in which 5-LO inhibition consistently ameliorates hepatic steatosis, inflammation and fibrosis. Herein, we report the findings in mice with targeted deletion of Alox5 as a proof of concept of the role of 5-LO in liver injury. Our findings demonstrate that ablation of Alox5 in mice confers protection against carbon tetrachloride-induced liver injury since hepatic necroinflammation, inflammatory infiltrate, hepatocyte ballooning and serum ALT levels were significantly reduced in Alox5-deficient mice. These mice also showed a lower degree of hepatic steatosis, which affected micro- and macrosteatosis to a similar extent. Moreover, microarray analysis revealed a differential profile of hepatic gene expression in Alox5-deficient mice, with a total of 117 genes differentially expressed in these animals. Functional grouping of these genes revealed that 28 (approximately 24% of total changes) were related to the category of lipid metabolism, including the lipogenic factors Lpin1, C/EBP, Fasn, Acly and Elovl6. Moreover, Ingenuity Pathway Analysis revealed lipid metabolism as the molecular/cellular function most affected by the loss of Alox5. These findings confirm at a genetic level that Alox5 plays a pathogenic role in the response of the liver to injury.
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PMID:Protection from hepatic lipid accumulation and inflammation by genetic ablation of 5-lipoxygenase. 2022 14


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