Uric acid formation

Allopurinol is an inhibitor of uric acid formation, administered to some gout patients. 

The usual initial dose is 2 mg/kg daily hy the oral route. If there is no clinical improvement or leukopenia after 4 weeks the dosage is increased to 3 mg/kg daily. In contrast to mercaptopurine, thioguanine may be continued in the usual dose when allopurinol is used to inhibit uric acid formation. 

Uric acid is the chief end product of purine metabolism in primates, birds, lizards, and snakes. An inborn metabolic error in humans results in increased levels of uric acid and its deposition as painful crystals in the joints. This condition (gout) may be treated by the drug allopurinol which is also oxidized by xanthine oxidase to allo-xanthine (dashed line in Eq. 19.29). However, alloxanthine binds so tightly to the molybdenum that the enzyme is inactivated, the catalytic cycle broken, and uric acid formation is inhibited. The extra stability of the alloxanthine complex may be a result of strong N—H --N hydrogen bonding by the nitrogen in the 8-position ... 

Figure 19. Blockade of uric acid formation by allopurinol...

Ans A In chronic gout, the strategy is to decrease uric acid formation... 

Purines can be degraded to uric acid. They can also be salvaged prior to uric acid formation, with resynthesis of purine nucleotides. Excess uric acid formation can lead to gout. 

It has been observed that the drug is not uricosuric, but it does inhibit the production of uric acid by way of blocking categorically the biochemical reactions that are essentially involved immediately preceding uric acid formation. Hence, it also inhibits xanthine oxidase (enzyme), which is exclusively responsible for the conversion of hypoxanthine to xanthine and of xanthine ultimately to uric acid. 

Drugs That Decrease Uric Acid Formation... 

The importance of the avian liver in the synthesis of uric acid became dear as the result of two early experiments (see Baldwin, 1967). When geese were hepatectomised, there was a rapid rise in the concentration of ammonia in the blood and when goose liver was perfused with ammonia, the formation of uric acid could be detected. The biosynthetic pathway leading to uric add formation shares many of the enzymes required for the purine precursors of the purine nucleotides. The three steps that are distinct for uric acid formation are the conversion of... 

In order to evaluate the influence of nutrition on uric acid formation and eventual excretion, adequate methods must be used. They may be based on two different principles, those of metabolic balance on the one hand and isotope incorporation and subsequent dilution on the other. 

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). 

The enzyme activity was estimated spectrophotometrically at 295 nm by determining uric acid formation (U-32I0 Hitachi) with xanthine as substrate (20). The enzyme reaction system consisted of a I mL reaction mixture containing 0.1 M potassium phosphate buffer pH 7.4, 0.004U XO and xanthine as substrate. All inhibitors were preincubated with enzyme for 3 min, then reaction was started by addition of xanthine. The reference cuvette was identical and only em e was absent. The ICSO and equations of dose-response curves were analyzed by computer with Sigma plot. 

Studies with labeled lactic acid demonstrated that the carboxyl and a-carbons of lactate were converted into carbons 4 and 5 of uric acid, respectively. Since CO2 is the specific precursor of Ce, it was thought that lactic acid was converted into a 2-carbon compound prior to its utilization for uric acid formation. In view of the demonstration by Shemin of the conversion of serine to glycine, it was postulated that lactate was converted to serine which was then degraded to glycine, the latter being the more immediate purine precursor. This was confirmed by experimental evidence when high isotope concentrations were found in C4 after administration of carboxyl-labeled glycine. 

---