Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.17.3.2 (xanthine oxidase)
 8,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recently, we demonstrated elevated levels of xanthine oxidase in serum of patients with various inflammatory and autoimmune rheumatic diseases. The present study reports the antiarthritic efficacy of the xanthine oxidase inhibitor and immunosuppressant allopurinol in DBA/1xB10A(4r) mice suffering from peroxochromate-induced arthritis. A profound dose-dependent suppression of arthritis was noted (P < 0.001). The ED50 was 80 +/- 14 mumol/kg/day. The arthritis index correlated positively to the phagocytic production of oxygen radicals (r2 > 0.672) and negatively to the concentrations of allopurinol (r2 = 0.915). Ex vivo, allopurinol and various conventional antirheumatic drugs were screened for the inhibition of 12-O-tetradecanoylphorbol-13-acetate-stimulated whole human blood chemiluminescence. The concentrations of antirheumatic drugs required to inhibit the chemiluminescence by 50% were compared to the therapeutic doses administered to rheumatic patients. While D-penicillamine and cis-platinum(II) increased the phagocytic generation of superoxide, nonsteroidal antiinflammatory drugs (NSAIDs), steroids, and slow-acting antirheumatic drugs (SAARDs) inhibited the whole blood chemiluminescence in a dose-dependent manner. Therapeutic doses of NSAIDs, SAARDs, or steroids inhibited the phagocytic generation of reactive oxygen species by 10-50%. In addition to well-known mechanisms of action of NSAIDs and SAARDs, our results support the hypothesis that most common anti-rheumatic drugs act also by modulating the levels of reactive oxygen species, which serve important mediator and signal transduction functions in inflammatory and autoimmune diseases. Pharmacologically safe antioxidants like allopurinol, which simultaneously modify the oxidative burst of phagocytes, inhibit xanthine oxidase, and display immunosuppressive effects may well be suited to control the consequences of chronic phagocytic hyperreactivity in rheumatic patients.
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PMID:Effects of allopurinol on in vivo suppression of arthritis in mice and ex vivo modulation of phagocytic production of oxygen radicals in whole human blood. 784 3

Mouse molybdo-flavoenzymes consist of xanthine oxidoreductase, aldehyde oxidase (AOX1), and two recently identified proteins, AOH1 and AOH2 (aldehyde oxidase homologues 1 and 2). Here we demonstrate that CD-1, C57BL/6, 129/Sv, and other mouse strains synthesize high levels of AOH1 in the liver and AOH2 in the skin. By contrast, the DBA/2 and CBA strains are unique, having a selective deficit in the expression of the AOH1 and AOH2 genes. DBA/2 animals synthesize trace amounts of a catalytically active AOH1 protein. However, relative to CD-1 animals, an over 2 log reduction in the steady-state levels of liver AOH1 mRNA, protein, and enzymatic activity is observed in basal conditions and following administration of testosterone. The DBA/2 mouse represents a unique opportunity to purify AOX1 and compare its enzymatic characteristics to those of the AOH1 protein. The spectroscopy and biochemistry of AOX1 are very similar to those of AOH1 except for a differential sensitivity to the non-competitive inhibitory effect of norharmane. AOX1 and AOH1 oxidize an overlapping set of aldehydes and heterocycles. For most compounds, the substrate efficiency (V(max)/K(m)) of AOX1 is superior to that of AOH1. Alkylic alcohols and acetaldehyde, the toxic metabolite of ethanol, are poor substrates of both enzymes. Consistent with this, the levels of acetaldehyde in the livers of ethanol administered CD-1 and DBA/2 mice are similar, indicating that neither enzyme is involved in the in vivo biotransformation of acetaldehyde.
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PMID:Regulation and biochemistry of mouse molybdo-flavoenzymes. The DBA/2 mouse is selectively deficient in the expression of aldehyde oxidase homologues 1 and 2 and represents a unique source for the purification and characterization of aldehyde oxidase. 1466 39