Subject xanthine oxidase

Superoxide is formed (reaction 1) in the red blood cell by the auto-oxidation of hemoglobin to methemo-globin (approximately 3% of hemoglobin in human red blood cells has been calculated to auto-oxidize per day) in other tissues, it is formed by the action of enzymes such as cytochrome P450 reductase and xanthine oxidase. When stimulated by contact with bacteria, neutrophils exhibit a respiratory burst (see below) and produce superoxide in a reaction catalyzed by NADPH oxidase (reaction 2). Superoxide spontaneously dismu-tates to form H2O2 and O2 however, the rate of this same reaction is speeded up tremendously by the action of the enzyme superoxide dismutase (reaction 3). Hydrogen peroxide is subject to a number of fates. The enzyme catalase, present in many types of cells, converts... 

Table 8.2 Effects of sodium selenite (Se) on mechanical performance of hearts under is-chemia/reperfusion (I/R), or perfused with xanthine plus xanthine oxidase (X + XO), or hydrogen peroxide (H2O2), or subjected to Ca2+ paradox model...

Molybdenum plays a role in several enzyme reactions. Some of the molybdenum-containing enzymes are aldehyde oxidase, sulfite oxidase, xanthine dehydrogenase, and xanthine oxidase. This metal is found in cereal grains and legumes leafy vegetables, especially those rich in chlorophyll animal organs and in relatively small amounts, less than 0.1 ppm, in fruits. The molybdenum content of foods is subject to large variations. 

Disposition in the Body. Rapidly absorbed after oral administration bioavailability about 90%. The major metabolite, oxypurinol (alloxanthine), is active but less potent than allopurinol. Subjects with a genetic deficiency of xanthine oxidase are unable to metabolise allopurinol to oxypurinol. The excretion of unchanged drug appears to vary with acute or chronic... 

Five proteins containing molybdenum are known nitrate reductase, nit-rogenase, xanthine oxidase, aldehyde oxidase and sulphite oxidase. They also contain iron, and the first four are best classified as multi-enzyme systems. Early studies on xanthine oxidase used a number of important ESR techniques, particularly rapid freeze kinetic methods and isotopic substitution in metalloproteins. This work has been reviewed [38, 39], Nitrogenase is the subject of considerable recent interest since it contains detectable iron-sulphur centres but as there is some disagreement at present concerning the interpretations of the results readers are referred to the original literature [40-42]. 

Tn recent years there has been an increased interest in assessing the human health effects from environmental exposure to trace metals. Studies of occupational exposures and dietary intakes of trace metals have required the refinement and development of analytical techniques for the analyses of low elemental concentrations in complex matrices. Molybdenum is one of the trace metals that has been the subject of intensive study because it is an essential trace element in both plant and animal nutrition. It is an integral constituent of several metalloenzymes including xanthine oxidase, which is the last enzyme in the catabolic pathway of purines. Extensive ingestion of molybdenum has been shown to cause molybdenosis in cattle. Many of the features of this condition can be ascribed to induced copper deficiency. Whether biochemical changes or adverse health effects in humans can be attributed to excessive exposure to molybdenum is not known. 

Fig. 10. Glycated Cu,Zn-SOD in streptozotocin-induced diabetic rat lens. Pooled lenses from normal and streptozotocin-induced diabetic rats [9 weeks after intravenous injection of streptozotocin (STZ)] were homogenized, and Cu,Zn-SOD was extracted by chloroform/ethanol and subjected to a boronate affinity column. Upper panel, normal rat lens lower panel, diabetic rat lens. The SOD activity and immunoreactive Cu,Zn-SOD were measured using the xanthine/xanthine oxidase method and ELISA, respectively.

Spectrophotometric analysis of urinary inhibition on the active forms (HMW-UK and LMW-UK) revealed a significant difference between subjects with and without renal calculi (VI). A positive correlation exists between the percentage of inhibition and the urinary urate concentration. Urate inhibits both the LMW-UK and the HMW-UK, but not plasmin. These results are in perfect agreement with reports that stone patients have higher urinary urate concentrations (C2). These observations may explain why allopurinol is administered to kidney stone patients. Allopurinol causes a decrease in urinary urate excretion by inhibiting the xanthine oxidase, which could cause a higher urinary urokinase activity. 

The oxidation of substituted benzaldehydes by xanthine oxidase is sterically hindered by bulky substituents at the ortho (o) position (Table 3.5) [167], Increasing the size of the halo-substituent dramatically decreases the oxidation of the o-substituted compound, whereas that of the p-halobenzaldehyde increases due to the increased inductive effect. The positional specificity was not due to electronic effects, because the oxidation rate was also decreased with electron-donating o-substituents. Although the substrates of aldehyde oxidase have not been so rigourously examined, the enzyme does appear to be subject to similar steric considerations, as o-chloro- and o-nitrobenzaldehyde are oxidized at much lower rates than benzaldehyde itself [33]. 

Xanthine oxidase in the small intestine and liver converts mercaptopurine to thiouric acid, which is inactive as an immunosuppressive. Inhibition of xanthine oxidase by allopurinol diverts mercaptopurine to more active metabolites such as 6-thioguanine and increases both immunosuppressive and potential toxic effects. Thus, patients on mercaptopurine should be warned about potentially serious interactions with medications used to treat gout or hyperuricemia, ami the dose should be decreased to 25% of the standard dose in subjects who are already taking allopurirwl. 

Besides, allopurinol, inhibits de novo purine synthesis V7a a feedback mechanism, that specifically provides another benefit to the subject. It is found to get metabolized by xananthine oxidase to oxypurinol, that also invariably inhibits xanthine oxidase. However, oxypurinol possesses a much longer half-clearance time from plasma than allopurinol. 

Examination of the urine of patients with this disease reveals in addition to the high uric acid an elevated hypoxanthine to xanthine ratio (L4). Furthermore, it was found that upon the administration of allopuri-nol, an inhibitor of xanthine oxidase that is widely used in the treatment of gout, the total output of purine is not reduced. This is in contrast to the reduction in total oxypurine output seen in normal or most gouty individuals. In addition, the ratio of hypoxanthine to xanthine is not reduced i.e., Lesch-Nyhan patients still maintained elevated hypoxanthine to xanthine ratios. These data have suggested an interference with hypoxanthine metabolism or reutilization, since the reduction in purine output after aUopurinoI therapy is due to anabolism of the hypoxanthine to inosinate (B4). It was shown by Seegmiller and his associates that there was an absence of hypoxanthine phosphoribosyltransferase in the red cells of subjects with Lesch-Nyhan syndrome. 

When 12 healthy subjects were given famciclovir 500 mg after taking allopurinol 300 mg daily for 5 days there were no clinically relevant changes in the pharmacokinetics of either drug. It was concluded that xanthine oxidase does not play an important role in the metabolism of famcielovir to peneielovir. ... 

Xanthine oxidase does not act on biopterin (Forrest et al., 1956). The pattern of urinary excretion of biopterin might be expected, therefore, to differ not only from that of xanthopterin, but also from uric acid. The excretion of uric acid is elevated in leukemia, perhaps reflecting (Krakoff, 1957) an acceleration of nucleic acid ssmthesis. If this acceleration entailed parallel increases in the folic acid and other cofactors for making nucleic acid, then it would account for the increased excretion of xanthopterin in leukemia noted earlier. The turnover of biopterin in leukemia and in normal subjects is, one must emphasize, entirely unknown. 

Conversion of xanthine dehydrogenase to an oxidase form has been suggested to be important in ischemia/reperfusion injury, and its role has been the subject of much speculation and investigation (for a review see Nishino, 1994). Conversion of the dehydrogenase to the oxidase during ischemia has been proposed to leave the vascular endothelium predisposed... 

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