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:1.11.1.7 (peroxidase)
65,474 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ability of nonsteroidal anti-inflammatory drugs to exacerbate experimental colitis, and the possible contributions of the "shunting" of arachidonate via the 5-lipoxygenase pathway, were investigated using a rat model in which colitis was induced by intracolonic administration of trinitrobenzene sulfonic acid in a vehicle of 50% ethanol. Twice daily treatment with indomethacin (0.1-1 mg/kg SC) during the first week after trinitrobenzene sulfonic acid/ethanol administration resulted in dose-dependent increases in the severity of colitis and in the incidence of mortality. Mortality was not observed in vehicle-treated colitic rats or in normal rats treated with indomethacin. Similar exacerbation of colitis was observed in rats treated with naproxen (5 mg/kg). Whereas treatment with a 5-lipoxygenase inhibitor, PF-5901 (100 mg/kg PO), resulted in a significant reduction of the severity of colitis, concomitant administration of PF-5901 and indomethacin (0.5 mg/kg SC) did not inhibit the exacerbative effects of the indomethacin in this model. In separate studies, administration of indomethacin was found to significantly increase colonic myeloperoxidase activity (a measure of tissue granulocyte numbers) and suppress colonic prostaglandin E2 synthesis, while not significantly affecting colonic leukotriene B4 synthesis. The effect on myeloperoxidase activity was seen during the period 21-24 hours after trinitrobenzene sulfonic acid ethanol administration, but not during the period 45-48 hours after induction of colitis. In in vitro studies using samples of inflamed colon and in vivo studies in which colonic eicosanoid production was measured by colonic dialysis, inhibition of prostaglandin E2 synthesis was not accompanied by significant changes in leukotriene B4 synthesis. These results suggest that inhibitors of colonic prostaglandin synthesis can markedly exacerbate colitis, and that this effect is unrelated to alterations in colonic leukotriene B4 synthesis. Endogenous prostaglandins may exert anti-inflammatory effects during the acute stages of colitis.
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PMID:Exacerbation of experimental colitis by nonsteroidal anti-inflammatory drugs is not related to elevated leukotriene B4 synthesis. 130 57

The in vitro synthesis of leukotriene B4 (LTB4) was evaluated in colorectal biopsy specimens and resection tissue from patients with inflammatory bowel disease. The in vitro formation of LTB4 from biopsy tissues stimulated with calcium ionophore A23187 correlated with the degree of mucosal inflammation assessed at sigmoidoscopy, and with neutrophil infiltration measured as myeloperoxidase activity. Biopsy specimens from patients taking prednisolone formed less LTB4 than those from patients not on prednisolone, with comparable levels of inflammation seen at sigmoidoscopy. The formation of LTB4 was reduced dose-dependently by the acetohydroxamic acid 5-lipoxygenase inhibitor BWA4C, with no significant inhibition of prostaglandin E2 or thromboxane B2 synthesis. In inflamed colonic resection tissue from colitic patients, the IC50 for inhibition of LTB4 formation by BWA4C was 0.03 mumol/l, compared with an IC50 of 0.8 mumol/l for NDGA. Thus, BWA4C is a potent and selective inhibitor of LTB4 synthesis in colonic tissue from patients with ulcerative colitis. Acetohydroxamic acid 5-lipoxygenase inhibitors, exemplified by BWA4C, may be useful to evaluate the clinical importance of LTB4 in ulcerative colitis, and offer a novel therapy for the disease.
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PMID:Colorectal leukotriene B4 synthesis in vitro in inflammatory bowel disease: inhibition by the selective 5-lipoxygenase inhibitor BWA4C. 131 5

Four oxygenases of the arachidonic acid cascade (cyclooxygenase, 5-lipoxygenase, 12-lipoxygenase and 15-lipoxygenase) were investigated by the method of computer-assisted sequence comparison. From the calculations, some aspects of evolution and function of these enzymes were revealed. (1) The evolutionary origin of cyclooxygenase was different from that of lipoxygenases. (2) Cyclooxygenase was a distantly related member of a peroxidase family. (3) Enzymes with 12-lipoxygenase activity were created independently twice by gene duplication.
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PMID:Molecular evolution of cyclooxygenase and lipoxygenase. 143 82

The immunohistochemical distribution of arachidonate lipoxygenases in rat pancreas was characterized with specific polyclonal anti-5-lipoxygenase and anti-12-lipoxygenase antibodies. Immunohistochemical analysis of formaldehyde-fixed paraffin-embedded rat pancreas using anti-12-lipoxygenase antibody and biotin-avidin-peroxidase detection demonstrated specific staining of islets and no staining of pancreatic exocrine tissue. Less intense staining of pancreatic vascular myocytes and endothelial cells was also observed. Immunoblotting of isolated pancreatic islet extracts with the anti-12-lipoxygenase antibody demonstrated immunoperoxidase staining of a single protein band which comigrated with purified 12-lipoxygenase (relative molecular weight = 72,000) on sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis. Dispersed cells prepared from isolated islets and then subjected to fluorescence-activated cell sorting and immunostaining exhibited 12-lipoxygenase antigen in beta-cell populations but not in non-beta-cell (predominantly alpha-cell) populations. Assays of enzymatic activity confirmed that the 12-lipoxygenase-catalyzed conversion of arachidonic acid to 12-hydroxyeicosatetraenoic acid methyl ester occurred only with purified beta-cells and not with islet non-beta-cells. No evidence of 5-lipoxygenase antigen or enzymatic activity was found in purified beta-cells or in islet non-beta-cells. We conclude that rat pancreatic islet beta-cells contain an arachidonate 12-lipoxygenase which shares antigenic epitopes with the homologous enzyme contained in tissues from other species. In addition, the selective localization of the 12-lipoxygenase to pancreatic beta-cells and its absence in pancreatic acinar cells and in islet non-beta-cells support observations suggesting that 12-lipoxygenase products may participate in glucose-induced insulin secretion from beta-cells.
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PMID:Selective expression of an arachidonate 12-lipoxygenase by pancreatic islet beta-cells. 144 14

Reactive oxygen metabolites (ROMs) are involved in inflammatory diseases and are postulated to contribute to tissue injury in colitis. To determine whether excessive ROMs are generated by inflamed colonic mucosa and to identify possible sources and type of ROMs, mucosal ROMs were estimated in rats and humans using a chemiluminescence probe. Colitis was induced in rats by intracolonic injection of acetic acid or intraperitoneal injection of mitomycin C. Intact, inflamed colon in rats produced more ultraweak chemiluminescence than normal colon. Inflamed mucosal scrapings from both rat models produced significantly more luminol-enhanced chemiluminescence. Addition of catalase, an H2O2 scavenger, or azide, a myeloperoxidase inhibitor, into the media significantly decreased chemiluminescence from inflamed mucosal scrapings. Indomethacin, an antioxidant cyclo-oxygenase inhibitor, also decreased chemiluminescence, but MK-866, a 5-lipoxygenase inhibitor, had no effect. Colonic biopsy specimens obtained during colonoscopy from patients with ulcerative colitis also produced more catalase-inhibitable chemiluminescence than normal colonic mucosa. These data indicate that excessive ROMs are produced by inflamed colonic mucosa in both humans and rats, which may contribute to tissue injury.
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PMID:Excessive production of reactive oxygen metabolites by inflamed colon: analysis by chemiluminescence probe. 161 25

Participation of microcirculatory disturbances, especially the role of 5-lipoxygenase products from neutrophils, was investigated in indomethacin (Indo)-induced ulcers of rat small intestine. After Indo treatment (20 mg/kg) in rats, small erosions appeared at 6 h and longitudinal ulcers developed 12 h later. At 6 and 12 h after Indo treatment, severe microcirculatory disturbances were observed under an intravital fluorescence microscope. Significant delay in the clearance and patchy pooling of injected fluorescein isothiocyanate-bovine serum albumin with sludge and stasis were observed in archade vessels of villi of Indo-treated rats. Increased numbers of sticking leukocytes were also detected along submucosal venules in these rats after the infusion of acridine orange. When regional venous blood was collected from the mesentery, a marked increase in neutrophil number and their increased production of oxygen-derived free radicals as determined by chemiluminescence assay were demonstrated at 6 h after Indo treatment. There was also a significant increase in myeloperoxidase activity of the intestinal mucosa at 6 and 12 h after Indo treatment, suggesting a significant neutrophil accumulation at this time. AA-861, a selective inhibitor of 5-lipoxygenase (80 mg/kg), attenuated these microcirculatory changes and neutrophil accumulation in the intestinal mucosa. AA-861 also significantly prevented the formation of intestinal ulcers induced by Indo. However, Indo-induced ulcer formation and leukocyte accumulation in submucosal venules were not attenuated by the treatment of Ono-1078, a potent antagonist of sulfidopeptide leukotrienes. From these observations, it is considered that microcirculatory disturbances, especially leukocyte accumulation and 5-lipoxygenase products, possibly leukotriene B4, may be involved in the development of Indo-induced intestinal ulcer.
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PMID:Microcirculatory disturbance in indomethacin-induced intestinal ulcer. 165 57

Inhibition of soybean lipoxygenase (L-1) and potato 5-lipoxygenase (5-PLO) by the pyrazoline derivatives phenidone and BW755C only occurs after oxidation of these compounds by the peroxidase-like activity of the lipoxygenases. There is a clear relationship between this oxidation and the irreversible inactivation of L-1. The final product of phenidone oxidation by L-1, 4,5-didehydrophenidone, is not responsible of this inactivation, but the species derived from a one-electron oxidation of phenidone plays a key role in L-1 inactivation. In the absence of O2, inactivation of 1 mol of L-1 occurs after the oxidation of 34 mol of phenidone and the covalent binding of 0.8 mol of phenidone-derived metabolite(s) to L-1. In the presence of O2, inactivation of 1 mol of L-1 occurs already after oxidation of 11 mol of phenidone and only involves the covalent binding of 0.4 mol of phenidone-derived metabolite(s) to L-1. A mechanism is proposed for L-1 inactivation by phenidone, which involves the irreversible binding of a phenidone metabolite to the protein and the oxidation of an L-1 amino acid residue (in the presence of O2).
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PMID:Mechanisms of inactivation of lipoxygenases by phenidone and BW755C. 165 81

Leukotriene B4 (LTB4) is the major 5-lipoxgenase product released during early experimental glomerulonephritis. To test its functional relevance, its actions in the normal rat kidney and its influence on renal function in the heterologous phase of mild nephrotoxic serum-induced glomerular injury were examined. Intrarenal administration of leukotriene B4 resulted in mild vasorelaxant and natriuretic responses which were shared by 12(R)-hydroxyeicosatetraenoic acid but not 12(S)-leukotriene B4 or 12(S)-hydroxyeicosatetraenoic acid, suggesting activation of a common recognition site with a requirement for 12(R) stereochemistry. The polymorphonuclear cell-specific activator, N-formyl-Met-Leu-Phe, stimulated leukotriene B4 production from isolated perfused kidneys harvested from nephrotoxic serum-treated rats to a significantly greater degree than from control animals treated with nonimmune rabbit serum. The renal production of leukotriene B4 correlated directly and strongly (r = 0.79, P less than 0.01) with renal myeloperoxidase activity, suggesting interdependence of leukotriene B4 generation and polymorphonuclear cell infiltration. In vivo, intrarenal administration of leukotriene B4 to rats with mild nephrotoxic serum-induced injury was associated with an increase in polymorphonuclear cell infiltration, reduction in renal plasma flow rate, and marked exacerbation of the fall in glomerular filtration rate, the latter correlating strongly with the number of infiltrating polymorphonuclear cells/glomerulus, whereas inhibition of 5-lipoxygenase led to preservation of glomerular filtration rate and abrogation of proteinuria. Thus, although devoid of vasoconstrictor actions in the normal kidney, increased intrarenal generation of leukotriene B4 during early nephrotoxic serum-induced glomerular injury amplifies leukocyte-dependent reductions in glomerular perfusion and filtration rates, likely due to enhancement of polymorphonuclear cell recruitment/activation.
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PMID:Functional significance of leukotriene B4 in normal and glomerulonephritic kidneys. 165 93

Granulocyte diapedesis in response to the generation of defined chemotaxins such as leukotriene B4 (LTB4), 12(R)-hydroxyeicosatetraenoic acid [12(R)-HETE], C5a, platelet activating factor and others is a hallmark of the inflammatory process that is thought to contribute to the tissue pathology seen in a number of diseases. 6-trans-LTB4 arises through the myeloperoxidase (MPO)-dependent metabolism of sulfidopeptide leukotrienes and through the action of 5-lipoxygenase on 12(R)-HETE. The intradermal (i.d.) injection of 6-trans-LTB4 induces a dose and time dependent influx of granulocytes into the guinea-pig (Hartley) dermis. When various doses of the LTB4 receptor antagonist and antiinflammatory agent, SC-41930 (7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)-propoxy]-3,4-dihydro- 8-propyl-2H-1-benzopyran-2-carboxylic acid) given 30 min ahead of i.d. injection of 6-trans-LTB4 (10 micrograms/i.d. site), granulocyte infiltration, as assessed by dermal levels of the neutrophil marker enzyme MPO was inhibited with an ED50 value of 9.8 mg/kg in the guinea-pig. When various doses (10-25 micrograms) 6-trans-LTB4 were injected in the mouse (CD-1) dermis, there was a dose-related increase in granulocyte accumulation at 4 h. Furthermore when mice were pretreated (-30 min) with SC-41930 (1 mg/kg) orally, the trafficking of granulocytes was inhibited (p less than .01) as assessed by dermal MPO levels. SC-41930 orally inhibits 6-trans-LTB4-induced granulocyte accumulation in the guinea-pig more potently than against the response to 12(R)-HETE(ED50:13.4 mg/kg) but less potently than against LTB4 (ED50:0.6 mg/kg). These multiple activities may contribute to this compound's potential as an inflammatory agent.
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PMID:The antiinflammatory agent SC-41930 inhibits granulocyte infiltration of the rodent dermis induced by 6-trans-leukotriene B4. 165 13

The role of endogenously released eicosanoids in intraocular inflammation was assessed in two rabbit models. The models were: (1) paracentesis in which only breakdown of blood-aqueous barrier (BAB) occurs and (2) uveitis induced by endotoxin in which the disruption of the BAB and polymorphonuclear leukocyte infiltration are the predominant events. Indomethacin (a specific cyclooxygenase inhibitor) applied topically inhibited both the disruption of the BAB and increased levels of aqueous humor 6-keto-Prostaglandin (PG)F1 alpha. However, indomethacin and flurbiprofen applied topically and BWA4C or BWA218C (both selective lipoxygenase inhibitors) given parenterally, did not inhibit BAB response in endotoxin-induced uveitis. The cyclooxygenase inhibitors attenuated PGE2 release into aqueous humor. The 5-lipoxygenase inhibitors reduced the PMN infiltration as well as LTB4 release into aqueous humor. However, myeloperoxidase activity (an index for PMN chemotaxis) in iris-ciliary body was not affected by these drugs. Furthermore, concentrations of LTB4 in aqueous humor after paracentesis and uveitis-induced by endotoxin were similar, although in the former model there was no leukocyte infiltration, but in the latter model this leukocyte response was predominant. The results of this study suggest that locally released autocoids may not initiate ocular inflammation and other mediators such as cytokines may be involved in the inflammatory responses of the rabbit eye. We tried to detect IL-1 activity in aqueous humor following endotoxin. However, we could not detect the presence of IL-1-like activity, possibly because endotoxin also releases PGs, which inhibit IL-1 bioassay.
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PMID:The role of endogenous eicosanoids in rabbit-intraocular inflammation. 166 45


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