Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.13.11.12 (lipoxygenase)
 8,696 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A cytochrome P-450 was isolated from a fungus, Fusarium oxysporum, which grew on a medium containing soybean oil as a sole carbon source. It was found as a heme protein that possess lipoxygenase activity, and seemed to exist in the soluble fraction of cell-free extracts. The cytochrome revealed multiplicity and could be separated into a least 3 fractions (A, B, and C). Two of them, termed Fusarium P-450A and -B, were highly purified. The complex of the ferrous Fusarium P-450 with carbon monoxide showed a Soret peak at 447 nm. The properties of the cytochromes (P-450A and -b) were closely similar to each other, the only detectable difference being in the pI (isoelectric point) value (5.2 and 5.0, respectively). The pI and molecular weight (48,000) values together with amino acid composition of Fusarium P-450 were similar to those of other cytochromes P-450 from various sources. Some other spectral properties as well as interactions with various ligands were also studied. Peroxidase or chloroperoxidase activity was not detected with Fusarium P-450.
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PMID:Purification and properties of a cytochrome P-450 of a fungus, Fusarium oxysporum. 665 54

Ketoconazole, cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate, and gossypol are reported inhibitors of the lipoxygenase (LO) and cytochrome P-450 enzyme systems and are potent blockers of swelling-activated efflux of organic osmolytes and volume-sensitive anion channels in C6 glioma cells. To directly test the hypothesis that LO- or cytochrome P-450-derived products of arachidonic acid (AA) participate in the regulation of these volume-sensitive transport pathways, we incubated C6 cells with [1-14C]AA and observed the extent and profile of its conversion under basal conditions and after acute swelling. High-performance liquid chromatographic analysis revealed that most (70-80%) of the labeled AA remained unchanged with only 6-8% and 10-20% of label converted to LO- [12(S)- and 15(S)-hydroxyeicosatetraenoic acid (12- and 15-HETE)] and cyclooxygenase- [prostaglandin (PG) E2 and PGF2a] derived products, respectively. Leukotrienes and epoxyeicosatrienoic acid compounds were not produced. The conversion profile of [1-14C]AA was not altered substantially by cell swelling. Treatment of cells with the LO-derived products 5-, 12-, and 15-HETE or their immediate metabolic precursors, 5(S)-, 12(S)-, and 15(S)-hydroxyperoxyeicosatetraenoic acid, at 5 microM concentrations did not stimulate efflux of [3H]inositol. In addition, treatment with HETEs did not override the inhibition of efflux observed with the LO-cytochrome P-450 blocker ketoconazole. Whole cell patch-clamp experiments demonstrated that volume-sensitive anion channels, the postulated pathway for organic osmolyte efflux in C6 cells, are rapidly and reversibly blocked by ketoconazole in a fashion suggestive of direct inhibition rather than via interruption of a second messenger pathway.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Ketoconazole blocks organic osmolyte efflux independently of its effect on arachidonic acid conversion. 751 97

Recently we have demonstrated that in rat pancreatic acini the high affinity cholecystokinin receptors are coupled to the phospholipase A2 (PLA2)/arachidonic acid (AA) cascades to mediate Ca2+ oscillations and amylase secretion. This intracellular signal transduction system is associated with an unidentified G protein(s) which is neither Gi/Go nor Gq-alpha. Using a newly cloned PLA2-activating protein (PLAP), we further examined the mechanisms by which PLA2 activates Ca2+ oscillation and pancreatic enzyme secretion. In intact acini, 0.1-1 microM PLAP evoked Ca2+ oscillations in a dose-dependent manner (delta [Ca2+]i: 18-121 nM and frequency: 2.3-5.5 cycles/10 min). PLAP elicited a 3-fold increase in monophasic amylase secretion with an EC50 of 0.1 microM. PLAP dose-dependently caused an increase in the AA metabolite 15-HETE. The PLA2 inhibitor, but not inhibitors of lipoxygenase, cytochrome P-450 and cyclooxygenase, inhibited the action of PLAP, suggesting that AA, but not AA metabolites, functions as a signal messenger. In permeabilized acini, a monoclonal antibody of G protein beta subunits inhibited the action of PLAP. Because of the structural similarity between PLAP and Gbeta protein we hypothesize that the PLA2 coupled G protein is Gbeta and it elicits Ca2+ oscillations and monophasic amylase secretion via the AA pathway.
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PMID:A newly cloned phospholipase A2-activating protein elicits Ca2+ oscillations and pancreatic amylase secretion via mediation of G protein beta/phospholipase A2/arachidonic acid cascades. 752 92

The metabolism of arachidonic acid (AA) into vasoactive products by cyclooxygenase and lipoxygenase enzymes has been well described, as has their biological relevance. Recently, a number of studies have demonstrated the ability of cytochrome P-450 (P450) enzymes to metabolize AA into biologically important regulators of vascular tone. There are two categories of vasoactive P450 metabolites, namely those catalyzed by epoxygenase enzymes which generate epoxyeicosatrienoic acids (EETs) and those enzymes which generate hydroxyeicosatetraenoic acids (HETEs). Except for 20-HETE, P450 metabolites of AA occur as stereo- and regioisomers which determine, to some extent, their biological activity. 5,6-, 8,9-, 11,12- and 14,15-EETs are generally potent dilators in a number of vascular beds with a sensitivity which appears to increase as the vasculature decreases in size toward capillaries. HETEs, such as 12R- and 20-HETE, can be potent activators of vascular tissue with 20-HETE contracting cerebral and renal microvessels at concentrations of < 10(-10) M. Both EETs and HETEs can be made by vascular and extravascular tissue. Available data suggests that EETs are formed by endothelial and parenchymal tissue while HETEs can be endogenously formed in arterial muscle where they appear to act as second messengers. This review will discuss the molecular biology, stereochemistry, biological activity and importance of P450 metabolites of AA as para- and autocrine controllers of organ blood flow. We will also discuss the large diversity of P450 enzyme isoforms and how such diversity can provide for precise physiological control of vascular tone.
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PMID:Role of cytochrome P-450 enzymes and metabolites of arachidonic acid in the control of vascular tone. 753 44

Endothelium-dependent relaxations to bradykinin (BK) in U46619-contracted, indomethacin (INDO)-treated porcine coronary artery (PCA) rings are modestly attenuated by the nitric oxide (NO) synthase inhibitor, N omega-nitro-l-arginine methyl ester (L-NAME); whereas, when contracted with KCl, L-NAME abolishes BK relaxations. In contrast, endothelium-dependent arachidonic acid (AA) relaxations of U46619-contracted, INDO-treated PCA rings are not affected by L-NAME. AA does not relax KCl-contracted rings. Since BK is known to release AA, we postulated that the non-NO component of BK relaxation of the PCA is mediated by AA or an AA metabolite. Changes in tension of PCA rings to BK and AA were determined in the presence and absence of phospholipase (PLA), cyclooxygenase (CO), lipoxygenase (LO) and cytochrome P-450 (cP450) inhibitors. Responses to BK were attenuated by PLA inhibitors. No other inhibitors, however, eliminated responses to either BK or AA. The results suggest that relaxation to BK in PCA rings requires PLA activity, but relaxation to AA is independent of PLA, CO, LO or cP450 activity. We conclude that relaxation to BK and AA in the PCA is mediated by a product of an unidentified pathway of AA metabolism or by an unknown second messenger system resident within the endothelium and responsive to AA.
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PMID:Endothelium-dependent relaxation to arachidonic acid in porcine coronary artery: is there a fourth pathway? 762 May 17

Cellular signalling by the inflammatory cytokine tumour necrosis factor alpha (TNF alpha) has been suggested to involve generation of low levels of reactive oxygen species (ROS). Certain antioxidants and metal chelators can inhibit cytotoxicity and gene expression in response to TNF alpha in numerous cell types. However, neither the source nor function of TNF alpha-induced oxidant generation is known. Using specific inhibitors, we ruled out involvement of several oxidant-generating enzymes [cyclo-oxygenase (indomethacin), cytochrome P-450 (metyrapone), nitric oxide synthase (NG-methyl-L-arginine), NADPH oxidase (iodonium diphenyl), xanthine oxidase (allopurinol), ribonucleotide reductase (hydroxyurea)] in TNF alpha-mediated apoptosis of the murine fibrosarcoma line, L929. We also demonstrated no role for mitochondrial-derived radicals/respiratory chain in the lytic pathway using specific inhibitors/uncouplers (rotenone, KCN, carboxin, fluoroacetate, antimycin, malonate, carbonyl cyanide p-trifluoromethoxyphenylhydrazone) and chloramphenicol-derived respiration-deficient cells. Significant ROS (H2O2, O2-.) generation was not observed in response to TNF alpha in L929 cells using four separate assays. Also, prevention of intracellular H2O2 removal by inhibition of catalase did not potentiate TNF alpha-mediated cell death. These data suggest that neither H2O2 nor O2-. plays a direct role in TNF alpha cytotoxicity. Finally, we suggest a central role for lipoxygenase in TNF alpha-mediated lysis. Three inhibitors of this radical-generating signalling pathway, including an arachidonate analogue (5,8,11,14-eicosatetraynoic acid), could protect cells against TNF alpha. The inhibitor nordihydroguaiaretic acid is also a radical scavenger, but it could not protect cells from ROS toxicity at concentrations that effectively prevented TNF alpha killing. Therefore protection by nordihydroguaiaretic acid cannot be due to scavenging of cytotoxic H2O or O2-.. The lipoxygenase product, (12S)-hydroxyeicosatetraenoic acid, was also significantly protective. As this analogue can act as a substrate for certain lipoxygenases, this effect may be due to prevention of generation of physiological products.
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PMID:Involvement of oxidants and oxidant-generating enzyme(s) in tumour-necrosis-factor-alpha-mediated apoptosis: role for lipoxygenase pathway but not mitochondrial respiratory chain. 764 35

The clinical pharmacology of all-trans retinoic acid (RA) has distinct differences from that of its widely studied stereoisomer 13-cis retinoic acid (cRA). RA is much more rapidly cleared from plasma following oral administration; their respective half-lives are < 1 h and 13 h. There is extensive accumulation of the 4-oxo-cRA in plasma following repeated doses of cRA, while 4-oxo-RA is only a minor metabolite in plasma following RA administration. The extent of isomerization in vivo differs for the two retinoids. In contrast to cRA, where up to a 1:3 ratio of RA to cRA is observed in patient plasma following drug administration, cRA concentrations in excess of 10 ng/ml are rarely observed in plasma of patients receiving exogenous RA. RA administration produces autoinduction of its own oxidative catabolism; this effect does not occur with cRA. These pharmacokinetic differences have been observed in leukemia and solid tumor patients. Detailed analysis of the results of the population studied suggest that both constitutive and RA-induced hypercatabolism of RA occurs. Both of these hypercatabolic states can be modulated by concurrent administration of ketoconazole, an inhibitor of cytochrome P-450 and lipoxygenase-mediated oxidations.
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PMID:Clinical pharmacology of all-trans retinoic acid. 780 19

Basic and clinical investigations into the roles of arachidonate-derived compounds in regulating renal function under normal and pathophysiological conditions continued to expand over the past year. Exciting new insights regarding the pathobiology of thromboxane A2 revealed new roles for this potent cyclooxygenase-derived vasoconstrictor in the glomerular dysfunction that accompanies inflammatory disorders and insulin-dependent diabetes. Major advances have extended our understanding of the proinflammatory actions of leukotriene B4 and other 5-lipoxygenase compounds in mediating glomerular injury during experimental glomerulonephritis. Intriguingly, emerging evidence suggests the presence of an anti-inflammatory arm in the lipoxygenase pathway, ie, 15-lipoxygenase, products of which may act as endogenous leukotriene antagonists. New information has also become available about the renal biology of cytochrome P-450 metabolites of arachidonic acid as well as about nonenzymatically generated biologically potent eicosanoids, the F2-isoprostanes.
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PMID:Arachidonate and renal function. 792 69

Arachidonic acid is metabolized via three major enzymatic pathways: cyclooxygenase, lipoxygenase, and cytochrome P-450. The cyclooxygenase pathway gives rise to the prostaglandins and thromboxane A2. The lipoxygenase pathway produces the leukotrienes and 5-, 12-, and 15-hydroxyeicosatetraenoic acids. The cytochrome P-450 pathway metabolites are oxygenated metabolites of arachidonic acid. Synthesis of several of the cyclooxygenase and lipoxygenase metabolites are increased in circulatory shock. A potential role for several of these compounds in the pathophysiologic sequelae of endotoxic and septic shock has been implied from a combination of animal and human studies. There are no studies that have explored a potential role for cytochrome P-450 metabolites in the pathogenesis of circulatory shock.
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PMID:Prostaglandins, thromboxanes, leukotrienes, and cytochrome P-450 metabolites of arachidonic acid. 792 94

Previous studies have shown that stimulating pituitary GH4C1 cells with thyrotropin-releasing hormone (TRH) evoked a biphasic change in cytosolic free Ca2+ concentration ([Ca2+]i): a rapid release of sequestered Ca2+ due to the production of inositol-1,4,5-trisphosphate, and Ca2+ entry via both voltage-operated Ca2+ channels and a presently unknown voltage-independent influx pathway. The aim of the present study was to further evaluate to which extent the TRH-evoked changes in [Ca2+]i were dependent on entry of extracellular Ca2+, and which mechanisms participated in regulating this Ca2+ entry. Pretreatment of the cells with 4-bromophenylacylbromide (an inhibitor of phospholipase A2), nordihydroguaiaretic acid (an inhibitor of lipoxygenase), and econazole (an inhibitor of both lipoxygenase and cytochrome P-450 enzymes), attenuated the TRH-evoked increase in [Ca2+]i, suggesting that noncyclooxygenase metabolites of arachidonic acid or cytochrome P-450 metabolites may participate in regulating the TRH-evoked entry of extracellular Ca2+. Both nordihydroguaiaretic acid and econazole showed a similar inhibition of the Ca2+ entry, as did SKF 96365, a compound previously shown to inhibit receptor-activated Ca2+ entry. We also showed that arachidonic acid per se increased [Ca2+]i, and acidified the cytosol in GH4C1 cells in a dose-dependent manner. The effects of arachidonic acid was reversed by addition of BSA to the cell suspension. The calcium entry and the activation of the metabolism of arachidonic acid may thus be important components of the TRH-evoked signal-transduction pathway in GH4C1 cells.
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PMID:TRH-evoked entry of extracellular calcium in GH4C1 cells: possible importance of arachidonic acid metabolites. 792 62


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