Uric acid formation from xanthine

Allopurinol is a uricosuric drug used in chronic gout that prevents formation of uric acid from purines by acting as a suicide substrate of xanthine oxidase. The drug is commonly used in patients undergoing treatment of cancer to slow down formation of uric acid derived from purines released by the cytotoxic action of drugs or radiation. The metabolism of 6-mercaptopurine (6-MP), a substrate for xanthine oxidase, is also inhibited by allopurinol, necessitating a major dose reduction to avoid its toxic effects. 

Figure 34-8. Formation of uric acid from purine nucleosides byway of the purine bases hypoxanthine, xanthine, and guanine. Purine deoxyribonucleosides are degraded by the same catabolic pathwayand enzymes,all of which existin the mucosa of the mammalian gastrointestinal tract.

Dietary purines are not an important source of uric acid. Quantitatively important amounts of purine are formed from amino acids, formate, and carbon dioxide in the body. Those purine ribonucleotides not incorporated into nucleic acids and derived from nucleic acid degradation are converted to xanthine or hypoxanthine and oxidized to uric acid (Figure 36-7). Allopurinol inhibits this last step, resulting in a fall in the plasma urate level and a decrease in the size of the urate pool. The more soluble xanthine and hypoxanthine are increased. 

Calcium and oxalate are closely associated with the formation of stones in the urinary tract. Kidney stones (renal calculi) and bladder stones are mineral deposits containing protein. They can have a diameter of a centimeter or greater. Most kidney stones (75%) are composed mainly of calcium oxalate or calcium oxalate with hydroxyapatite. Uric acid stones accoimt for about 10% of stones xanthine stones are rare. Calcium-containing kidney stones occur in Western nations and affect about one person in 1000. The disease may occur in children, but typically occurs after the age of 30 and in men. Calcium bladder stones occur mainly in the children of xmderdeveloped countries, such as Thailand, and occur rarely in Western nations. Some kidney stones do not result in symptoms. Others may cause blood loss in the urine. Stones that obstruct the flow of urine from the kidney into the ureter result in violent pain, nausea, and vomiting. 

Chronic gout is treated with allopurinol, a suicide inhibitor of xanthine oxidase the goal is to reduce the uric acid pool by inhibiting its formation from purines. The adverse effects of allopurinol are j considered. 

Fig. 5.7. Formation of hypoxanthine, xanthine and uric acid and their release from different avian tissues. The thicknesses of the arrows are indicative of the rates of release and uptake.

Adenosine formation is accelerated under hypoxic conditions (Rudolphi et al. 1992), but it is metabohsed only after reperfusion. Now superoxide dismutase and catalase are insufficient to serve detoxification of the reactive oxygen species resulting from the biotransformation of hypoxanthine to xanthine and of xanthine to uric acid. While xanthine oxidase inhibitors as oxypurinol do protect against ischaemic damage (Helfman and Phillis 1989, Lin and Phillis 1992), adenosine deaminase inhibitors as trazodone (Sheid 1985) are expected to reduce the formation of hypoxanthine and xanthine, the substrates for xanthine oxidase. 

Allopurinol therapy in hyperuricaemic man has been shown to be advantageous from two points of view. Firstly, it reduces urinary uric acid excretion and increases the excretion of the precursor purines xanthine and, to a lesser extent, hypoxanthine. In addition, total urinary purine excretion (the sum of these three) may be reduced by as much as 0 during allopurinol therapy (1). This latter effect has been attributed to the formation of nucleotides of either hypoxanthine (1) or allopurinol itself (2), which in turn exert a feed back inhibitary effect on the first enzyme of de novo purine synthesis. 

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