Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P47989 (xanthine oxidase)
 8,633 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

BAY X1005, (R)-2-[4-(quinolin-2-yl-methoxy)phenyl]-2-cyclopentyl acetic acid, is an enantioselective inhibitor of leukotriene biosynthesis. It effectively inhibits the synthesis of LTB4 in A23187-stimulated leukocytes from rats, mice and humans (IC50 0.026, 0.039 and 0.22 mumol/l, respectively) as well as the formation of LTC4 (IC50 0.021 mumol/l) in mouse peritoneal macrophages stimulated with opsonized zymosan. The compound is, however, less active in inhibiting LTB4 synthesis in human whole blood (IC50 17.0 and 11.6 mumol/l, as measured by RIA or HPLC, respectively). BAY X1005 exhibits a high enantioselectivity in human whole blood (31 times over the (S)-enantiomer). BAY X1005 is shown to be a selective inhibitor of the formation of 5-lipoxygenase-derived metabolites in vitro, without effects on other routes of arachidonic acid metabolism such as 12-lipoxygenase in human whole blood and cyclooxygenase in both mouse macrophages and human whole blood. BAY X1005 is devoid of any antioxidant activity (methemoglobin induction and xanthine-xanthine oxidase assay), without effects on granule release and with only weak effects on reactive oxygen species generation in human PMNL.
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PMID:In vitro pharmacology of BAY X1005, a new inhibitor of leukotriene synthesis. 821 45

Arachidonic acid is converted to 12-hydroxyeicosatetraenoic acid (12-HETE) in a homogenate of mouse epidermal cells. When the epidermal homogenate was preincubated with scavengers of reactive oxygen species (ROS), catalase or superoxide dismutase, significantly larger amounts of 12-HETE were produced as compared to untreated controls, suggesting that 12-lipoxygenase is quite prone to inactivation by ROS and peroxides. Mouse epidermal homogenate was then exposed to nine different ROS-generating systems to study the effects of superoxide, hydrogen peroxide, singlet oxygen, hypochlorite, peroxyl radicals, and alkyl hydroperoxides on the enzyme activity. Analysis by chiral phase high performance liquid chromatography demonstrated that the 12-HETE biosynthesized from arachidonic acid by mouse epidermal homogenate was the 12 (S)-enantiomer and excludes oxidation of arachidonic acid by ROS in a nonspecific free radical mechanism which leads to racemic 12-HETE. ROS generated by the interaction of xanthine with xanthine oxidase strongly inhibited epidermal 12 (S)-HETE biosynthesis. A flux of 0.7 nmol of superoxide/min/ml of reaction medium resulted in more than 50% inhibition of epidermal 12-lipoxygenase activity. The decrease in 12 (S)-HETE biosynthesis appeared to involve both superoxide and hydrogen peroxide. The efficacy of the latter species was also documented by exposure of mouse epidermal 12-lipoxygenase to glucose and glucose oxidase, which resulted in similar inhibitory effects on 12 (S)-HETE biosynthesis. The presence of the iron chelator diethylenetriaminepentaacetic acid during incubation of epidermal 12-lipoxygenase with both the xanthine/xanthine oxidase or the glucose/glucose oxidase systems partially protected the enzyme against inhibition, indicating that hydroxyl radical contributes to the overall inhibitory effect. Also, organic hydroperoxides inhibited epidermal 12-lipoxygenase, whereas singlet oxygen, hypochlorite, and peroxyl radicals were not effective. The results of this study lead to the proposal that 12-lipoxygenase activity may be regulated by ROS such as hydrogen peroxides, superoxide, and hydroxyl radicals.
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PMID:Effects of reactive oxygen species on the biosynthesis of 12 (S)-hydroxyeicosatetraenoic acid in mouse epidermal homogenate. 919 95

The effects of a new type of nitric oxide (NO)-releasing compound, 1-hydroxyl-2-oxo-3-(N-methyl-3-aminopropyl)-3-methyl-1-triazene (NOC7), and peroxynitrite (ONOO-) on the formation of 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE), thromboxane (TX) B2 and 12-hydroxy-5,8,10-heptadecatrienoic acid (HHT) from exogenous arachidonic acid in washed rabbit platelets have been compared. At concentrations of 5 microM and below, NOC7 inhibited 12-HETE formation (56.5-98.8% inhibition). Moreover, NOC7 inhibited TXB2 and HHT formation at concentrations ranging from 5 to 20 microM (TXB2, 62.2-88.1% inhibition; HHT, 11.6-62.2% inhibition). ONOO- had little or no effect on the production of these three metabolites at concentrations of up to 50 microM. Experiments utilizing a new class of NO antidote, carboxy-2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide, revealed that the observed effects of NOC7 are caused by NO. The effects of NO were reversed by addition of the superoxide generating system (xanthine plus xanthine oxidase and catalase), indicating that superoxide is a vital modulator of the action of NO. These results suggest that NO, but not ONOO- (up to 50 microM), can be a potent dual inhibitor of the 12-lipoxygenase and cyclooxygenase activities in platelets and that superoxide is an important regulator of the action of NO.
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PMID:Comparison of the effects of nitric oxide and peroxynitrite on the 12-lipoxygenase and cyclooxygenase metabolism of arachidonic acid in rabbit platelets. 977 72