Xanthine incorporation into nucleic acid purines

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. 

Allopurinol facilitates the incorporation of xanthine and hypoxanthine into nucleic acids, lowering the substrates for catabolism. In addition, the decrease in xanthine metabolism facilitates a negative feedback on purine synthesis. 

Hypoxanthine, on the other hand, which accounts for only a fifth or so of the urinary uric acid is an active intermediate. It is degraded to xanthine and then to uric add by xanthine oxidase. This enzyme is found mainly in liver, kidney, and bowel, while guanase is widely distributed and would quickly deaminate any guanine formed. The product xanthine is a poor substrate for hypoxanthine phosphoribosyltrans-ferase (HPRT). Most of the hypoxanthine formed is reutiliiced by conversion to inosinic acid. Similar conclusions were reached by Ayvazian and Skupp in 1965 when they administered C-labeled purines to patients (A2). Furthermore, these studies and those earlier studies show that the xanthine is converted to hypoxanthine, presumably at the nucleotide level, and on the basis of what we know about microorganisms, we would assume it to be via guanine nucleotides (M2). Since label was found in urinary 7-methylguanine as early as 4 hours after administration of C-labeled purines, and since methylation of RNA occurs at the macromolecular level (B13), interconversion must be rapid and incorporation of some of these products into nucleic acids must also occur quickly. 

It is also possible that the high xanthine oxidase activity of rat tissues was responsible for the nonutilization of hypoxanthine, since the base was extensively converted to allantoin (800). However, it is well known that hypoxanthine, as well as other purines, were also substrates for an anabolic enzyme system in the rat, namely, nucleoside phosphorylase (816). Hypoxanthine was readily utilized for the synthesis of both adenine and guanine of RNA and DNA in slices of rabbit bone marrow (808a), even though it was not incorporated into the nucleic acids of the rat (800). Bone marrow may lack xanthine oxidase, thus leaving hypoxanthine available to participate in synthetic reactions. Thus, the competition of several enzyme systems for the administered compound may have determined its final disposition. 

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