Inhibition of xanthine oxidase

Uricostatic drugs inhibit the production of uric acid through the inhibition of xanthine oxidase. Allopurinol is the only therapeutically used uricostatic drug. 

The ability of flavonoids (quercetin and rutin) to react with superoxide has been shown in both aqueous and aprotic media [59,94]. Then, the inhibitory activity of flavonoids in various enzymatic and nonenzymatic superoxide-producing systems has been studied. It was found that flavonoids may inhibit superoxide production by xanthine oxidase by both the scavenging of superoxide and the inhibition of enzyme activity, with the ratio of these two mechanisms depending on the structures of flavonoids (Table 29.4). As seen from Table 29.4, the data obtained by different authors may significantly differ. For example, in recent work [107] it was found that rutin was ineffective in the inhibition of xanthine oxidase that contradicts the previous results [108,109], The origins of such big differences are unknown. 

The absence of substituents with free radical scavenging properties in most of the (3-blockers makes doubtful their efficacy as powerful antioxidants. Arouma et al. [293] tested the antioxidative properties of several 3-blockers in reactions with superoxide, hydroxyl radicals, hydrogen peroxide, and hypochlorous acid. It was demonstrated that most of the compounds tested were inactive in these experiments. Nonetheless, propranolol, verapamil, and flunarizine effectively inhibited iron ascorbate-stimulated microsomal lipid peroxidation and all drugs (excluding flunarizine) were effective scavengers of hydroxyl radicals. Contrary to Janero et al. [292], these authors did not find the inhibition of xanthine oxidase by propranolol. It was concluded that 3-blockers are not the effective in vivo antioxidants. 

Ichimori, K., Fukahori, M., Nakazawa, H., Okamoto, K., Nishino,T., Inhibition of xanthine oxidase and xanthine dehydrogenase by nitric oxide. J. Biol. Chem. 274 (1999), p. 7763-7768... 

Values ( mmol I-1) of Flavonoids for the Inhibition of Xanthine Oxidase and Scavenging Superoxide Ion... 

Pharmacokinetics Allopurinol is completely absorbed after oral administration. The primary metabolite is alloxanthine (oxypurinol) which is also a xanthine oxidase inhibitor. The pharmacologic effect of administered allopurinol results from the combined activity of these two compounds. The plasma half-life of allopurinol is short (2 hours), whereas the half-life of oxypurinol is long (15 hours). Thus, effective inhibition of xanthine oxidase can be maintained with once daily dosage. The drug and its metabolite are excreted in the feces and urine. 

The percent inhibition of xanthine oxidase is determined relative to control solutions. 

Hille, R., and Stewart, R., 1984, The inhibition of xanthine oxidase by 8-bromoxanthine, J. Biol. Chem. 259 157091576. 

Lin, J.K., Chen, PC., Ho, C.T., and Lin-Shiau, S.Y., Inhibition of xanthine oxidase and suppression of intracellular reactive oxygen species in HL-60 cells by theaflavin-3,3 -digallate, (-)-epigallocatechin-3-gallate and propyl gallate, J. Agric. Food. Chem., 48, 2736-2743, 2000. 

Other Ca + sensitizing agents Inhibition of xanthine oxidase... 

Decreases uric acid production by inhibition of xanthine oxidase, an enzyme, reducing uric acid concentrations in both serum and urine. 

Inhibition of Xanthine Oxidase Uric acid, the end product of purine catabolism in humans, is formed by the serial oxidation of hypoxanthine and of xanthine, catalyzed by xanthine oxidase. 

Inhibition of xanthine oxidase by allopurinol, an analogue of hypoxanthine. Nv and Cg of hypoxanthine are reversed in allopurinol. Allopurinol, a suicide enzyme inactivator, is converted to alloxanthine, which binds tightly to the active site of the enzyme via Mo and interrupts the reoxidation of Mo + to Mo " needed to initiate the next catalytic cycle. 

Recurrences of acute gouty arthritis may be prevented with continuous low-dose daily oral colchicine or by uric acid-lowering therapy with either uricosuric agents or inhibition of xanthine oxidase with allopurinol. Combination therapy consisting of colchicine plus a uricosuric agent or allopurinol may be employed in resistant cases. The choice of treatment depends on the serum urate concentration, the amount of uric acid excreted in a 24-hour period, and the renal function stams of the patient. 

An interesting example of a DDI due to the inhibition of a non-CYP enzyme that can have serious clinical consequences is the inhibition of xanthine oxidase by allopu-rinol 6-mercaptopurine (6-MP) as an antimetabolite type of antineoplastic drug. One of its indications is in the treatment of inflammatory bowel disease. Actually, 6-MP is a prodrug whose active metabolite, 6-thiogua-nine (6-TG) is responsible for its therapeutic activity. Some nonresponders to 6-MP do not form sufficient amounts of 6-TG. A complementary pathway of 6-MP metabolism is oxidation to 6-thiouric acid (6TU), which is mediated by xanthine oxidase. Inhibition of this complementary pathway by allopurinol shunts the metabolism of 6-MP favoring increased formation of 6-TG. 

Table 3. Summnry of the Classification of Flavonoids into Six Categories According to their Inhibition of Xanthine Oxidase (XO) and Superoxide...

Guerrero RO, Guzman AL Inhibition of xanthine oxidase by Puerto Rican plant extracts. P R Health Sci... 

Kong LD, Cai Y, Huang WW, et al Inhibition of xanthine oxidase by some Chinese medicinal plants... 

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. 

A marked dose-dependent inhibition of xanthine oxidase activity by rutin (200-300 p,M) and narin-gin (200-400 iM) was shown in the xanthin-xanthine oxidase system, while the addition of cate-chin (200-400 iM) exhibited a lower effect on uric acid formation (Russo et al. 2000). 

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