Uric acid Oxidation products

Parks, D.A., Tan, S., Poplawski, S.C., Baldwin, S. and Sweeney, S.D. (1992). Uric acid oxidation products indicator of oxidant stress in human liver transplantation. Gastroenterology 102, A232. 

Fichter and Kern O first reported that uric acid could be electrochemically oxidized. The reaction was studied at a lead oxide electrode but without control of the anode potential. Under such uncontrolled conditions these workers found that in lithium carbonate solution at 40-60 °C a yield of approximately 70% of allantoin was obtained. In sulfuric acid solution a 63% yield of urea was obtained. A complete material balance was not obtained nor were any mechanistic details developed. In 1962 Smith and Elving 2) reported that uric acid gave a voltammetric oxidation peak at a wax-impregnated spectroscopic graphite electrode. Subsequently, Struck and Elving 3> examined the products of this oxidation and reported that in 1 M HOAc complete electrochemical oxidation required about 2.2 electrons per molecule of uric acid. The products formed were 0.25 mole C02,0.25 mole of allantoin or an allantoin precursor, 0.75 mole of urea, 0.3 mole of parabanic acid and 0.30 mole of alloxan per mole of uric acid oxidized. On the basis of these products a scheme was developed whereby uric acid (I, Fig. 1) is oxidized in a primary 2e process to a shortlived dicarbonium ion (Ha, lib, Fig. 1) which, being unstable, under-... 

Uric acid is one of the principal products of purine metabolism in man 12 13). However, in many other organisms further oxidative degradation of the purine molecule occurs. One of the most important enzymes involved in uric acid oxidation is uricase, which has been studied to some extent in vitro. 

A large number of products, including some of the products of uricase action, are produced from uric acid by peroxidases + enzymatically generated H202. The nonspecific action of peroxidases emphasizes the part played by nonenzymatic reactions of the unstable products of uric acid oxidation. 

Fig. 3. Primary electrochemical mechanism and products formed on oxidation of uric acid at the PGE in 1 M HOAc...

Table 2. Structures of proposed primary products or intermediates formed on oxidation of uric acid along with the major products of the oxidations...

In the case of the methylated xanthines, particularly theophylline, theobromine and caffeine, the preponderance of data on the metabolism of these compounds in man suggests that a methylated uric acid is the principal product. However, the data presented earlier proposes at best a 77 per cent accounting of the methylated xanthine administered. The question can be raised as to whether the final products observed upon electrochemical oxidation of these compounds aids these studies. Very recently studies of metabolism of caffeine have revealed that 3,6,8-trimethylallantoin is a metabolite of caffeine 48>. This methylated allantoin is, of course, a major product observed electrochemically. The mechanism developed for the electrochemical oxidation seems to nicely rationalize the observed products and electrochemical behavior. The mechanism of biological oxidation could well be very similar, although insufficient work has yet been performed to come to any definite conclusions. There is however, one major difference between the electrochemical and biological reactions which is concerned with the fact that in the former situation no demethylation occurs whereas in the latter systems considerable demethylation appears to take place. 

Uric acid is the end-product of purine metabolism in humans, other primates, birds and reptiles. It is produced in the liver by the oxidation of xanthine and hypoxanthine (Figure 12.16),... 

The amino groups are replaced with oxygen. Although here a biochemical reaction, the same can be achieved under acid-catalysed hydrolytic conditions, and resembles the nucleophilic substitution on pyrimidines (see Section 11.6.1). The first-formed hydroxy derivative would then tautomerize to the carbonyl structure. In the case of guanine, the product is xanthine, whereas adenine leads to hypoxanthine. The latter compound is also converted into xanthine by an oxidizing enzyme, xanthine oxidase. This enzyme also oxidizes xanthine at C-8, giving uric acid. 

As with adults, the primary organ responsible for drug metabolism in children is the liver. Although the cytochrome P450 system is fully developed at birth, it functions more slowly than in adults. Phase I oxidation reactions and demethylation enzyme systems are significantly reduced at birth. However, the reductive enzyme systems approach adult levels and the methylation pathways are enhanced at birth. This often contributes to the production of different metabolites in newborns from those in adults. For example, newborns metabolize approximately 30% of theophylline to caffeine rather than to uric acid derivatives, as occurs in adults. While most phase I enzymes have reached adult levels by 6 months of age, alcohol dehydrogenase activity appears around 2 months of age and approaches adult levels only by age 5 years. 

The addition of a phenylsulfoxide moiety to the end of the side chain markedly changes the activity of this class of compounds. This product, sulfinpyrazone (97-11), stimulates uric acid excretion, making it a valuable dmg for dealing with the elevated serum uric acid levels associated with gout. The compound is stiU one of the more important uricosuric agents available today. The starting ester (96-9) is available by alkylation of the dianion from ethyl malonate with 2-chloroethylphenyl thioether. Condensation with diphenylhydrazine (97-3) in the presence of a base then affords the pyrrazolodione (97-10). Oxidation of sulfur with a controlled amount of hydrogen peroxide leads to the sulfoxide and thus sulfinpyrazone (97-11) [107]. 

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