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 effects of allopurinol on the plasma clearance and metabolism of theobromine have been investigated under multiple-dosing conditions. Allopurinol had no effect on the clearance of theobromine, indicating that the elimination of this compound is dependent on enzyme systems other than xanthine oxidase, presumably the hepatic mixed-function oxidases. The excretion of 3-methylxanthine, 6-amino-5-(N-methylformylamino)-1-methyluracil, and unchanged theobromine were similarly unaffected by the allopurinol treatment. Although allopurinol abolished the formation of 7-methyluric acid (7MU) and increased the excretion of 7-methylxanthine (7MX), the metabolic clearance to (7MX + 7MU) was not significantly different with and without allopurinol. It is proposed that the secondary biotransformation of 7MX to 7MU is mediated by xanthine oxidase.
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PMID:Theobromine metabolism in man. 613 Sep 21

The hepatic metabolism of hypoxanthine was investigated by studying both the fate of labelled hypoxanthine, added at micromolar concentrations to isolated rat hepatocyte suspensions, and the kinetic properties of purified hypoxanthine/guanine phosphoribosyltransferase from rat liver. More than 80% of hypoxanthine was oxidized towards allantoin; less than 5% of the label was incorporated into the purine mononucleotides, and a similar proportion appeared transiently in inosine. The maximal velocity of oxidation (approx. 750nmol/min per g of cells) was in close agreement with the known activity of xanthine oxidase in liver extracts. In contrast, the maximal velocity of the incorporation of labelled hypoxanthine into mononucleotides reached only 30nmol/min per g of cells, compared with an activity of hypoxanthine/guanine phosphoribosyltransferase, measured at substrate concentrations analogous to those prevailing intracellularly, of 500nmol/min per g of cells. Hypoxanthine incorporation into the mononucleotides was decreased by allopurinol, anoxia and ethanol, despite inhibition of its oxidation under these conditions; it was increased by incubation of the cells in supraphysiological concentrations of Pi. Allopurinol and anoxia decreased the concentration of phosphoribosyl pyrophosphate inside the cells by respectively 40 and 60%, ethanol had no effect on the concentration of this metabolite and Pi increased its concentration up to 10-fold. The kinetic study of purified hypoxanthine/guanine phosphoribosyltransferase showed that a mixture of ATP, IMP, GMP and GTP, at the concentrations prevailing in the liver cell, decreased the V max. of the enzyme 6-fold, increased its Km for hypoxanthine from 1 to 4 microM and its Km for phosphoribosyl pyrophosphate from 2.5 to 25 microM. In the presence of 5 microM-hypoxanthine and 2.5 microM-phosphoribosyl pyrophosphate, the mixture of nucleotides inhibited the activity of purified hypoxanthine/guanine phosphoribosyltransferase by 95%. It is concluded that this inhibition results in a limited participation of hypoxanthine/guanine phosphoribosyltransferase in the control of the production of allantoin by the liver.
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PMID:Metabolism of hypoxanthine in isolated rat hepatocytes. 620 48

Metabolic flux through the purine salvage pathway appears to modulate superoxide secretion by elicited macrophages. Exogenous adenosine, the first substrate of this pathway, stimulates superoxide secretion, and Allopurinol, a specific inhibitor of xanthine oxidase, inhibits superoxide secretion. The effects of these agents are additive since it was possible for each to neutralize the effects of the other when given in combination. In these experiments, the purine salvage pathway was responsible for over ten times the superoxide production attributable to the NADPH oxidase system.
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PMID:Modulation of macrophage superoxide release by purine metabolism. 630 May 80

The results of animal experiments and clinical observations concerning the pathological role of hyperuricaemia and the effect of allopurinol treatment in acute metabolic disturbances and critically ill patients is reported. In uricase enzyme blocked rats treated by oxonic acid, urate nephropathy could be elicited by endogenous purine catabolism in shock. Hyperuricaemia aggravated the shock, while allopurinol increased the survival time. In shock resistant rats hyperuricaemia did not develop when shock was elicited. Allopurinol prevented hyperuricaemia and increased the physical performance of swimming rats, while in experimental DIC allopurinol reduced markedly the hyperuricaemia and the kidney damage. In clinical studies a close correlation was observed between the degree of hyperuricaemia and the severity of illness. Serum uric acid values were lowered in cases treated by peritoneal dialysis. In randomized control studies of newborns with IRDS the survival rate was improved by allopurinol treatment. In critically ill patients with various illnesses allopurinol prevented the progression of the pathological process and improved the clinical condition. The effect of allopurinol in acute clinical metabolic disturbances may be due to its protection against the renal damage by hyperuricaemia and against purine loss by inhibition of xanthine oxidase during the hypoxic stress and the enhancement of hypoxanthine salvage by HGPRT. Allopurinol reduced the production of superoxide radicals and thus the effect of injury may also be moderated by xanthine oxidase blockade.
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PMID:Role of hyperuricaemia in critically ill patients especially newborns. 638 36

Allopurinol was investigated in 3 x 6 cm congested island skin flaps in rats. Eight hours of venous occlusion produced total flap necrosis. Pretreatment with systemic allopurinol, an inhibitor of xanthine oxidase, enhanced the survival rate of hyperemic skin flaps. Xanthine oxidase activities were demonstrated in skin, and these enzyme activities were noted to increase in skin flaps during ischemia and reperfusion. Much of this increase in enzyme activity was prevented by allopurinol treatment. The xanthine oxidase system appears to be one of the sources of the superoxide radical, which may be involved in ischemic and reperfusion injury in skin.
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PMID:Effect of allopurinol on the survival of hyperemic island skin flaps. 654 51

We have investigated the possibility that xanthine oxidase-linked free radical production has a role in the genesis of arrhythmias during ischemia and reperfusion. In this study, rats were treated with allopurinol (20 mg/kg, orally, 24 hours before study, plus 20 mg/kg, iv, 15 minutes prior to study). Using an anesthetized open-chest preparation with either coronary artery occlusion for 30 minutes, or 5 minutes followed by 10 minutes reperfusion, we monitored and compared the rhythm disturbances in experimental vs. placebo-treated rats (n = 18 in each group). Allopurinol treatment reduced the incidence of ventricular tachycardia during ischemia from 88% to 50% (P less than 0.05) and the number of premature ventricular complexes from 471 +/- 120 to 116 +/- 46 (P less than 0.02), but the treatment had no effect upon the incidence or duration of ventricular fibrillation or upon mortality. In contrast, far more dramatic protection was observed during reperfusion after 5 minutes of ischemia. Allopurinol treatment reduced the incidence of ventricular fibrillation from 67% to 11% (P less than 0.01), reduced the mean duration of fibrillation from 230 +/- 70 to 14 +/- 1 seconds (P less than 0.05), and reduced mortality by half (10/18 to 4/18), although this did not reach a level of statistical significance. In addition, the mean duration of tachycardia was reduced from 83 +/- 26 to 38 +/- 8 seconds (P less than 0.05). Allopurinol pretreatment thus affords some protection against ischemia-induced arrhythmias, but a higher degree of protection against reperfusion-induced arrhythmias. Allopurinol inhibits xanthine oxidase activity, and, in turn, this inhibits superoxide radical production.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Ischemia and reperfusion-induced arrhythmias in the rat. Effects of xanthine oxidase inhibition with allopurinol. 654 76

High-energy phosphates in heart muscle deprived of oxygen are rapidly broken down to purine nucleosides and oxypurines. We studied the role of xanthine oxidase/dehydrogenase (EC 1.2.3.2/EC 1.2.1.37) in this process with novel high-pressure liquid chromatographic techniques. Under various conditions, including ischemia and anoxia, the isolated perfused rat heart released adenosine, inosine and hypoxanthine, and also substantial amounts of xanthine and urate. Allopurinol, an inhibitor of xanthine oxidase, greatly enhanced the release of hypoxanthine. From the purine release we calculated that the rat heart contained about 18 mU xanthine oxidase per g wet weight. Subsequently, we measured a xanthine oxidase activity of 9 mU/g wet wt. in rat-heart homogenate. When endogenous low molecular weight inhibitors were removed by gel-filtration, the activity increased to 31 mU/g wet wt. Rat myocardial xanthine oxidase seems to be present mainly in the dehydrogenase form, which upon storage at -20 degrees C is converted to the oxidase form.
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PMID:Myocardial xanthine oxidase/dehydrogenase. 657 31

Earlier studies suggested that the dose of 6-mercaptopurine (6-MP) can be reduced substantially when the drug is given with allopurinol. We studied the effect of allopurinol on the kinetics of oral and intravenous 6-MP. Studies conducted initially in rhesus monkeys and subsequently in man with 6-MP doses of 100 mg/m2 and 75 mg/m2, demonstrated that allopurinol pretreatment resulted in a nearly 400% increase in peak plasma concentration of oral 6-MP in monkeys (from a mean of 0.54 microM to a mean of 2.1 microM) and a 500% increase in man (0.74 microM to 3.7 microM). Allopurinol pretreatment also led to a 300% increase in plasma AUC in monkeys after oral 6-MP (from a mean of 121 microM/min to a mean of 391 microM/min) and a 500% increase in AUC in man (from a mean of 142 microM/min to a mean of 716 microM/min). In contrast, allopurinol pretreatment had no effect on the kinetics of intravenous 6-MP. This difference was found to be due to inhibition of first-pass metabolism of oral 6-MP as the result of the action of allopurinol on liver or intestinal xanthine oxidase. Our results indicate that, although dose reduction of oral 6-MP given in conjunction with allopurinol is appropriate, it is not necessary when 6-MP is injected intravenously.
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PMID:Inhibition of first-pass metabolism in cancer chemotherapy: interaction of 6-mercaptopurine and allopurinol. 658 97

The rate of purine de novo synthesis from sodium formate in developing rat brain falls in the late gestational stages to birth, rises again in the 1st week of life and then decreases rapidly to the 3rd week, and continues declining up to 8 weeks of life (adulthood). The changes in the overall purine biosynthetic rate with respect to time are similar to those in the activity of the rate-limiting enzyme [amidophosphoribosyltransferase (phosphoribosyl diphosphate amidotransferase; EC 2.4.2.14)]. Azaserine [O-diazoacetyl-L-serine], a known inhibitor of glutamine requiring metabolic steps, inhibits purine de novo synthesis by more than 90%. This confirms that the method used to assess purine de novo synthesis in fact does so. The effects of virazole [1-beta-ribofuranosyl-1-H,1,2,4-triazole-3-carboxamide], an inhibitor of IMP dehydrogenase (EC 1.2.1.14), and of alanosine [L-2-amino-3-(hydroxynitrosamino)propanoic acid] an inhibitor of adenylosuccinate synthetase (EC 6.3.4.4), on the rate of purine de novo synthesis were investigated in liver and brain tissue. The effect of the xanthine oxidase inhibitor allopurinol [4-hydroxypyrazolo(3,4-d)pyrimidine] was also investigated in liver tissue. The biosynthesis of the purines which were extruded into the incubation medium as well as those which remained in the tissue was studied. Only inhibitory effects were observed, and these were confined to the purines remaining in the tissue. Allopurinol was completely inert from this viewpoint. The results are compared with those of other workers using lymphoid cells, and emphasize the differences in the control of de novo purine synthesis in different tissues and under different conditions.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Purine de novo synthesis in liver and developing rat brain, and the effect of some inhibitors of purine nucleotide interconversion. 662 51

Intravenous allopurinol was administered in a dose of 5-10 mg/kg daily with continuous control of the blood level of the drug and its active metabolite in 12 infants or children in critical condition resulting from various illnesses. Only one died of the patients who were all in shock and whose state stagnated or progressed in spite of the usual intensive therapy. The importance of hyperuricaemia before treatment is emphasized as this is a common characteristic of hypoxic states and through urate nephropathy it further aggravates the course of the illness. Allopurinol may exert its beneficial effect not only by decreasing hyperuricaemia, but also by preventing the loss of purines from the hypoxic cells of the ischaemic tissues by inhibition of xanthine oxidase and/or diminishing the cytotoxic superoxide radical production, the source of which is xanthine oxidase.
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PMID:Effect of parenteral allopurinol treatment in critically ill children in need of intensive care. 667 Oct 68


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