Disease relevance of Xdh

• However, pretreatment with the macrophage toxicant GdCl(3), the xanthine oxidase (XO) inhibitor allopurinol, and the Fe(III) chelator Desferal resulted in a marked decrease in free radical generation, lung inflammation, and lung injury [1].
• Of considerable importance is that granuloma formation in the liver was poorly developed by treatment with either XO inhibitors or L-NMMA [2].
• The role of superoxide anion (O2-) and nitric oxide (NO) in the host defense mechanism against Salmonella typhimurium (LT-2) was examined by focusing on xanthine oxidase (XO) as an O2(-)-generating system and on inducible NO synthase (iNOS) [2].
• In influenza virus infection in mice, the level of xanthine oxidase (XO) at the infected sites was elevated to a great extent [3].
• During hypoxia (11% O(2)), only sickle mice converted tissue xanthine dehydrogenase to oxidase [4].

High impact information on Xdh

• PURPOSE: In this study, xanthine dehydrogenase, an enzyme structurally similar to xanthine oxidase, was assessed for its ability to activate mitomycin C [5].
• Oxygen consumption studies showed that xanthine dehydrogenase-activated mitomycin C consumed oxygen at a much lower rate than xanthine oxidase-activated mitomycin C [5].
• Lastly, treatment with allopurinol (an inhibitor of XO) and with chemically modified superoxide dismutase (a scavenger of O2-) improved the survival rate of influenza virus-infected mice [6].
• The activities of adenosine deaminase (ADA) and xanthine oxidase (XO), which generates O2-, were elevated in the s-BALF, lung tissue homogenate, and serum (plasma) [6].
• These results indicate that generation of oxygen-free radicals by XO, coupled with catabolic supply of hypoxanthine from adenosine catabolism, is a pathogenic principle in influenza virus infection in mice and that a therapeutic approach by elimination of oxygen radicals thus seems possible [6].

Chemical compound and disease context of Xdh

• Sustained inhibition of XO activity by p.o. administration of allopurinol did not inhibit the TPA-induced hyperplasia as determined histologically [7].
• Administration of hypoxanthine, a substrate of XO, at 33 mg/kg body weight i.p. 12 h after the administration of PEG-XO (0.6 unit/mouse, i.v.) resulted in significant suppression of tumor growth (P < 0.001), with no tumor growth even after 52 days [8].
• The non-phorbol ester tumor promoter benzoyl peroxide also elevated XO activity consistent with the degree of induced hyperplasia [7].
• Neither tosylphenylalanyl chloromethyl ketone nor retinoic acid, inhibitors of promotion Stages I and II, respectively, had significant effects on TPA-induced hyperplasia or elevated XO activity [7].
• The antiinflammatory steroid fluocinolone acetonide, an inhibitor of TPA-induced hyperplasia, as well as the multiple stages of tumor promotion as defined in SENCAR mice (Stages I and II), inhibited the TPA-dependent elevation of epidermal XO activity [7].

Biological context of Xdh

• Comparison of the deduced amino acid sequence of the mouse XD with those of the Drosophila and the rat homologues shows a high conservation of this protein (55% identity between mouse and Drosophila, and 94% identity between mouse and rat) [9].
• XD was found to be a single-copy gene approximately 70 kb long with 36 exons containing the transcribed sequence [10].
• The locus encoding the XD gene (designated Xd) was mapped to the distal part of mouse chromosome 17 by haplotype analysis of 114 interspecific backcross mice [10].
• A second region, centering around Slc8a1 and Xdh, also was affected by gene amplification but to a lesser extent [11].
• Aerobically but not hypoxically, MMC reduction by XDH followed Michaelis-Menten kinetics [12].

Anatomical context of Xdh

• These effects were concomitant with the inhibition of XO activity in BAL, suggesting that the activated macrophages and the activity of XO contributed to the generation of free radicals caused by DEP and LPS [1].
• The elevations were most remarkable in s-BALF and in lung tissue: We found a 170-fold increase in ADA activity and a 400-fold increase in XO activity as measured per volume of alveolar lavage fluid [6].
• Immunocytochemical and enzymatic analysis of XO in thoracic aorta and liver tissue of SCD mice showed increased vessel wall and decreased liver XO, with XO concentrated on and in vascular luminal cells [13].
• However, the high binding affinity of XO to blood vessels would cause systemic vascular damage and hence limits the use of native XO in clinical settings [8].
• XO is a secreted enzyme which is formed in the liver as xanthine dehydrogenase (XDH) and binds to the vascular endothelium [14].

Associations of Xdh with chemical compounds

• Protein synthesis de novo is not required for the elevation of XD mRNA after IFN-alpha treatment, since cycloheximide does not block the induction [9].
• Poly(I).poly(C) also induces XD mRNA in several other tissues in vivo [9].
• Radical adduct formation was suppressed by aminoguanidine, N-(3-aminomethyl)benzylacetamidine (1400W), or allopurinol, suggesting a role for both inducible nitric oxide synthase (iNOS) and xanthine oxidase (XO) in free radical formation [15].
• TNFalpha and LPS both increased NO2 in GPTE cells, but none of the Ca++-mobilizing agents nor p + XO significantly affected intracellular RNS [16].
• TNFalpha and LPS significantly increased intracellular oxidant production in GPTE cells, as did p + XO, but none of the cNOS activators affected production of oxidants in these cells [16].

Other interactions of Xdh

• We speculate that Btn1a1 functions either as a structural protein or as a signaling receptor by binding to xanthine dehydrogenase/oxidase [17].
• Cytokines increased NADPH oxidase activity in both wildtype and iNOS(-/-) hearts, whereas NADH oxidase and xanthine oxidase/xanthine dehydrogenase activities were unaffected [18].
• Curcumin possesses anti-inflammatory activity and is a potent inhibitor of reactive oxygen-generating enzymes such as lipoxygenase/cyclooxygenase, xanthine dehydrogenase/oxidase and inducible nitric oxide synthase [19].
• Aryl hydrocarbon receptor (AhR)-mediated induction of xanthine oxidase/xanthine dehydrogenase activity by 2,3,7,8-tetrachlorodibenzo-p-dioxin [20].

Analytical, diagnostic and therapeutic context of Xdh

• Molecular cloning of a cDNA coding for mouse liver xanthine dehydrogenase. Regulation of its transcript by interferons in vivo [9].
• Western blot and enzymatic analysis of liver tissue from SCD mice revealed decreased XO content [13].
• Localization of xanthine dehydrogenase mRNA in horse skeletal muscle by in situ hybridization with digoxigenin-labelled probe [21].
• The digoxigenin-labelled probe was produced by PCR with primers based on the cDNA sequence of mouse XDH and horse lung cDNAs [21].
• While MDA and XO levels are significantly lower, SOD level is significantly higher in the PTZ+erdosteine group compared to PTZ and control groups (P<0.01) [22].

References