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)

The toxic effect and anti-tumor activity of B-3839, a new molecular combination of pyrimidine antimetabolite 5-fluorouracil (5-FU) with the alkylating agent N-Chloroethyl-N-nitrosourea (BCNU), was compared to that of BCNU and 5-FU given alone and in physical combination. The tumor inhibitory effect of B-3839 was similar to that of BCNU given alone or combined with a low dose of 5-FU in the i.m. Walker tumor model. Furthermore, the bone marrow toxicity of BCNU was not significantly altered by either form of combination with 5-FU. The intestinal side effects, evaluated by measuring the decrease of marker enzyme (thymidine kinase, xanthine oxidase, alkaline phosphatase, sucrase, maltase) activities in isolated enterocytes, were dose-dependent and moderate. A significant, more than 30%, decrease occurred only if BCNU and 5-FU were given simultaneously or as B-3839. The molecular combination of the two drugs does not provide any additional advantage over their physical combination.
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PMID:Comparison of tumor growth inhibitory and toxic effects of a new fluorouracil--nitrosourea derivative (B-3839). 297 32

Regulation of induced nitric oxide synthase in rat hepatocyte primary cultures was explored. Nitric oxide synthase (NOS) induction by tumor necrosis factor-alpha (TNF alpha) is synergized by interferon-gamma, and both NOS activity and gene expression are maximal by 10 h and maintained through 24 h. Glutathione depletion by diethylmaleate, which conjugates reduced glutathione, 1,3-bis(chloroethyl)-1-nitrosourea (BCNU), a glutathione reductase inhibitor, or buthionine sulfoxamine, a glutathione synthesis inhibitor, abolishes or reduces NOS induction in TNF alpha-treated hepatocytes, whereas N-acetylcysteine has little effect. Thus, reduced glutathione is critical to NOS mRNA induction and activity in TNF alpha-treated hepatocytes. NOS induction in TNF alpha-treated cells is reduced by rotenone, a mitochondrial complex 1 inhibitor. Concurrent treatment with TNF alpha and the antioxidant, Trolox, or the iron-chelating agent, desferrioxamine, also reduces NOS activity. Dithiothreitol, a thiol antioxidant, reduced TNF alpha induction of NOS. Trolox and BCNU, combined, blocked TNF alpha stimulation of NOS greater than either agent alone. These results suggest that TNF alpha increases mitochondrial production of reactive oxygen intermediates (ROI), which contributes to NOS induction. Hepatocytes exposed to extracellular ROI generation through a xanthine/xanthine oxidase superoxide-generating system expressed increased NOS activity and mRNA levels. NOS induction by superoxide also requires reduced glutathione since diethylmaleate blocks induction by xanthine/xanthine oxidase while N-acetylcysteine elevates NOS expression. Thus, the generation of ROI by cytokines or other physiological processes stimulates the induction of NOS and this process is regulated by cellular levels of reduced glutathione.
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PMID:Regulation of hepatic nitric oxide synthase by reactive oxygen intermediates and glutathione. 753 84

In the present study we have examined the potential role of xanthine oxidase (XO) in the intracellular oxidative stress induced by combinations of recombinant murine TNF alpha (rMuTNF alpha) and murine interferon-gamma (IFN gamma) in cultured mouse hepatocytes. IFN gamma alone and the combination of rMuTNF alpha and IFN gamma increased XO activity after a 4 hr exposure period. rMuTNF alpha alone increased XO activity only after 24 hr. At the later time point, the increased XO activity was accounted for by decreased XDH activity. However, the apparent conversion of XDH to XO cannot account for the early effects of rMuTNF alpha on hepatocyte function, particularly the onset of an oxidative stress (as indicated by efflux of GSSG from the hepatocytes). This effect is observed after two hours, and it is temporally the earliest sign of alteration of cellular function caused by rMuTNF alpha. Increased XO activity was not observed until 4 hr after treatment with rMuTNF alpha/IFN gamma. In addition, inhibition of XO activity with allopurinol did not ameliorate GSSG efflux from hepatocytes treated with the cytokines. However, the ATP depletion caused by the combination of rMuTNF alpha and IFN gamma and the cytotoxicity observed with the combined cytokines in cells pre-treated with BCNU (to inhibit glutathione reductase) was inhibited by allopurinol. These results show that the onset of oxidative stress in cultured mouse hepatocytes is not due to conversion of XDH to XO. However, events which follow the efflux of GSSG, such as ATP depletion and cytotoxicity in cells with impaired anti-oxidant defenses, may be partially due to increased XO activity, especially in cells treated with both rMuTNF alpha and IFN tau.
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PMID:The role of xanthine oxidase in oxidative damage caused by cytokines in cultured mouse hepatocytes. 796 49