Xanthine oxidase interaction with

Xanthine oxidase (XO) is not only an important biological source of ROS but also the enzyme responsible for the formation of uric acid associated with gout leading to painful inflammation in the joints. The XO inhibition effect by the enzymatically synthesized poly(catechin) increased as an increasing concentration of catechin units, while the monomeric catechin showed almost negligible inhibition effect in the same concentration range. ° This markedly amplified XO inhibition activity of poly(catechin) was considered to be due to effective multivalent interaction between XO and the condensed catechin units in the poly (catechin). 

Azathioprine, mycophenolate mofetil, and enteric-coated MPA are not metabolized through the CYP isozyme system therefore, they do not experience the same DDI profiles as cyclosporine, tacrolimus, and sirolimus. Azathioprine s major DDIs involve allopurinol, angiotensin-converting enzyme (ACE) inhibitors, aminosalicylates (e.g., mesalamine and sulfasalazine), and warfarin.11 The interaction with allopurinol is seen frequently and has clinical significance. Allopurinol inhibits xanthine oxidase, the enzyme responsible for metabolizing azathioprine. Combination of azathioprine and allopurinol has resulted in severe toxicities, particularly myelosuppression. It is recommended that concomitant therapy with azathioprine and allopurinol be avoided, but if combination therapy is necessary, the azathioprine doses must be reduced to one-third or one-fourth of the current dose. Use of azathioprine with the ACE inhibitors or aminosalicylates also can result in enhanced myelosuppression.11 Some case reports exist demonstrating that warfarin s therapeutic effects may be decreased by azathioprine.43-45... 

Fig. 3. Rapid Mo(V) EPR signals obtained on reducing xanthine oxidase at pH 10 with 15 moles of xanthine for 1 min. at about 20 °. The upper four spectra are at 9.1 GHz and the lower four at 34.4 GHz. a, a, c, 8 refer to H2O as solvent and b, b, d, d to D2O. a, b, c, d are computer simulations of the experimental spectra, a, b, c, d, respectively. The interpretation is that two species, each having exchangeable protons which interact with Mo(V), are responsible for the signals. For one of these (dotted complex type II) there are two equivalent interacting protons and for the other (dashed complex type I), two non-equivalent protons. These species are believed to correspond to two different complexes of reduced xanthine oxidase with xanthine. (Reproduced from ref. 78 see also Table 2 for the parameters of the signals.)...

So little is known about molybdenum enzymes other than milk xanthine oxidase that there is little to be said by way of general conclusions. In all cases where there is direct evidence (except possibly for xanthine dehydrogenase from Micrococcus lactilyticus) it seems that molybdenum in the enzymes does have a redox function in catalysis. For the xanthine oxidases and dehydrogenases and for aldehyde oxidase, the metal is concerned in interaction of the enzymes with reducing substrates. However, for nitrate reductase it is apparently in interaction with the oxidizing substrate that the metal is involved. In nitrogenase the role of molybdenum is still quite uncertain. 

Komiyama, T., Kikuchi, T., and Sugiura, Y., 1986, Interactions of anticancer quinone dmgs, aclacinomycin A, adriamycin, carbazilquinone, and mitomycin C, with NADPH-cytochrome P-450 reductase, xanthine oxidase and oxygen, J. Pharmacobiodyru 9 651-664. 

Hatano, T. et al., Effects of interactions of tannins with co-existing substances. VII. Inhibitory effects of tannins and related polyphenols on xanthine oxidase, Chem. Pharm. Bull., 38, 1224, 1990. 

A large number of studies devoted to metal-sulfur centers are motivated by the occurrence of such arrangements at the active site of various metalloenzymes [1-13]. Mononuclear complexes with Mo=0 func-tion(s) and possessing sulfur ligands in their coordination sphere have been extensively investigated since they can be seen as models of the active site of enzymes such as nitrate- and DM SO reductases or sulfite- and xanthine oxidases [1-4]. On the other hand, a large variety of mono-, di-, and polynuclear Mo—S centers have been synthesized in order to produce functional models of the Mo-nitrogenase since the exact nature (mono-, di- or polynuclear) of the metal center, where N2 interacts within the iron-molybdenum cofactor (FeMo—co) of the enzyme is still unknown [4-8]. 

MP is converted to an inactive metabolite (6-thiouric acid) by an oxidation reaction catalyzed by xanthine oxidase, whereas 6-TG undergoes deamination. This is an important issue because the purine analog allopurinol, a potent xanthine oxidase inhibitor, is frequently used as a supportive care measure in the treatment of acute leukemias to prevent the development of hyperuricemia that often occurs with tumor cell lysis. Because allopurinol inhibits xanthine oxidase, simultaneous therapy with allopurinol and 6-MP would result in increased levels of 6-MP, thereby leading to excessive toxicity. In this setting, the dose of mercaptopurine must be reduced by 50-75%. In contrast, such an interaction does not occur with 6-TG, which can be used in full doses with allopurinol. 

Barber, M. J., Siegel, L. M. Proton and electron affinities and magnetic interactions associated with the molybdenum flavin, and iron-sulfur centers of milk xanthine oxidase. In Flavins and flavoproteins (Massey, V., Williams, C. H. eds.) pp. 796-804, New York, Amsterdam, Oxford, Elsevier/North Holland 1982... 

The role of these interesting plasma membrane-dependent, vanadate-stimulated NAD(P)H oxidation reactions in cellular metabolism remains to be elucidated, although multiple interactions with cellular metabolism and components are possible including interactions with xanthine oxidase and lipid peroxidation [24], Decavanadate has been shown to enhance cytochrome c reduction [31], and cytochrome c release from mitochondria is associated with initiation of apoptosis. Perhaps the reduced cytochrome c is more readily released from the mitochondria. With increasing emphasis on the redox properties of vanadium being important in its pharmacological effects, it is quite possible that these reactions, either protein dependent or not, may play a role in therapeutic actions of vanadium. 

An additional crucial piece of information emerges from the alloxan-thine study (24). Thus, it was shown that one alloxanthine binds to the enzyme per active molybdenum site. This result clearly implies that the molybdenum site is mononuclear. If a dinuclear site were involved, then it would be unlikely to require two alloxanthine molecules for inhibition and would be expected to be at least partially inhibited with one alloxan-thine/two molybdenum. Also, a difference in binding constant would be expected for the second compared with the first bound alloxanthine, but none is found. This result, coupled with the lack of evidence for Mo(V)-Mo(V) spin-spin interactions in the EPR spectra, clearly implicates a mononuclear site, and it would seem that xanthine oxidase possesses two full catalytic units, each containing one molybdenum, one flavin, and two Fe2S2 units (20). Other molybdenum oxidases also contain paired prosthetic groups and subunits, and it is likely that they each have two catalytic units per molecule. 

Hille, R., and Stewart, R. C., 1984, The interaction of xanthine oxidase with 8-bromoxanthine, J. Biol. Chem. 259 1570nl576. 

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