Purine dietary purines

Human tissues can synthesize purines and pyrimidines from amphibolic intermediates. Ingested nucleic acids and nucleotides, which therefore are dietarily nonessential, are degraded in the intestinal tract to mononucleotides, which may be absorbed or converted to purine and pyrimidine bases. The purine bases are then oxidized to uric acid, which may be absorbed and excreted in the urine. While little or no dietary purine or pyrimidine is incorporated into tissue nucleic acids, injected compounds are incorporated. The incorporation of injected [ H] thymidine into newly synthesized DNA thus is used to measure the rate of DNA synthesis. 

The purines from which uric acid is produced originate from three sources dietary purine, conversion of tissue nucleic acid to purine nucleotides, and de novo synthesis of purine bases. 

Dietary purines play an unimportant role in the generation of hyperuricemia in the absence of some derangement in purine metabolism or elimination. 

Hyperuricemia may be produced by overproduction of uric acid or under-excretion of uric add by the kidneys. Kyperuricemia may progress to acute and chronic gouty arthritis if uric acid (monosodium urate) is deposited in joints and surrounding soft tissue, where it causes inflammation, Uric add is produced from excess endogenous purines as shown in Figure 1-18-5, and is also produced from dietary purines (digestion of nucleic acid in the intestine) by intestinal epithe-lia. Both sources of uric acid are transported in the blood to the kidneys for excretion in urine. 

Gouty arthritis is an inflammatory response to the deposition of monosodium urate monohydrate crystals secondary to hyperuricemia. It is called monosodium urate crystal deposition disease. Hyperuricemia is a serum urate concentration > 7 mg% in males and >6 mg% in females. Hyperuricemia results from overproduction (10-15% of individuals) or a renal excretion of urate lower than 400 mg uric acid/24 hours (85-90% of individuals). The urate under-excretors have a urate clearance of <6 ml/min or a urate to creatinine clearance ratio of <6%. The combination of a relative excess of dietary purine consumption together with urate under-excretion is often the basis for hyperuricemia. 

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. 

Degradation of dietary nucleic acids occurs in the small intestine, where a family of pancreatic enzymes hydrolyze the nucleotides to nucleosides and free bases. Dietary purines are generally converted to uric acid, and dietary pyrimidines are degraded to small compounds by the intestinal mucosal cells. 

If properly controlled, simple gout may have few adverse effects. However, the severe neurological symptoms of Lesch-Nyhan syndrome (Section E,2 of text)6 cannot be corrected by medication. Colchicine (Box 7-D), in a manner which is not understood, alleviates the painful symptoms of gout caused by the deposits of sodium urate in joints and tissues. It is also important to keep the dietary purine intake low and it is often necessary to inhibit xanthine oxidase. A widely used and effective inhibitor is the isomer of hypoxanthine known as allopurinol, which is taken daily in amounts of 100 -600 mg or more. 

Pyrimidines and purines derivatives act as bases and can be acquired through the diet. In particular, organ meats such as liver are a rich source of DNA and RNA. Most dietary purines are oxidized by enzymes to uric acid in the intestinal mucosa that is their excretory product in humans. The desease known as gout is related to high levels of uric acid in serum and the result of deposition of urate salts in various tissues. 

Dietary purines are largely catabolized in the gut, rather than used by the body for the synthesis of nucleic acids. The end-product of purine catabolism in humans is uric add. The diet accounts f[ir less than half of the uric add appearing in the bloodstream, Most of the plasma uric add, or urate, originates from catabolism of the purines synthesized by the body (endogenous purines). The major purines are adenine and guanine. They occur mainly as nucleotides, such as adenosine triphosphate (ATP) and guanosine triphosphate (GTP), and as parts of nucleic acids. For example, the adenine in (UvfA occurs as adenosine monophosphate, and the adenine in DNA occurs as deoxyadenosine monophosphate. 

Overproduction of uric acid can occur due to excessive de novo purine synthesis, excessive dietary purines, or the conversion of tissue nucleic acid to purine nucleotides. When these purines are metabolized, the by-products are converted to uric acid by the enzyme xanthine oxidase. Increased levels of uric acid result if the overproduction exceeds excretion. Underexcretion of uric acid can be due to defects in the renal tubular mechanisms that regulate uric acid levels in the body, causing decreased filtration, decreased secretion, or increased reabsorption. 

Fate of dietary nucieoproteins. Only the predominant reactions are shown. Dietary purines are mostly converted to uric acid. 

The purines from which uric acid is produced originate from three sources dietary purine, conversion of tissue nucleic acid to purine nucleotides, and de novo synthesis of purine bases. The purines derived from these three sources enter a common metabolic pathway leading to the production of either nucleic acid or uric acid. Under normal circumstances, uric acid may accumulate excessively if production exceeds excretion. The average human produces about 600 to 800 mg of uric acid each day. 

Several enzyme systems regulate purine metabolism. Abnormalities in these regulatory systems can result in overproduction of uric acid. Uric acid also may be overproduced as a consequence of increased breakdown of tissue nucleic acids, as with myeloproliferative and lymphoproliferative disorders. Dietary purines play an unimportant role in the generation of hyperuricemia in the absence of some derangement in purine metabolism or elimination. 

Fig. 3 The different response of serum uric acid levels to dietary purines in familial hyperuricemia compared with normal subjects.

After the effect of dietary RNA had been well established, Zollner and his co-workers (Griebsch and Zollner, 1971 Zollner et al., 1972) investigated the influence of different dietary purine compounds on uric acid metabolism. It was found that the size of the response depended on the source of the purines. For example the increase in serum and urine uric acid was less with DNA than that produced by RNA, while it was greater with nucleotides. When single cell protein was added to a standard diet, the effect was greater than that of DNA, but less than that of RNA, which was to be expected from... 

The response of serum and urine uric acid to different kinds of dietary purines v/as explained by the hypothesis that RNA and DNA have to be degraded to their nucleotides (and possibly nucleosides) prior to absorption, and that different absorption might be due to a different velocity of degradation. This results in a renai excretion of the purines administered orally of about 25 percent in the case of DNA, 50 percent with RNA, and 80 percent with nucleotides (Zollner et al., 1972). The conclusion drawn from these results was that only nucleotides are absorbed from the gut completely. 

To summarize the data on endogenous uric acid production and on purine supplementation experiments, it would appear that on an average diet about half the urinary uric acid and one-third of the plasma uric acid is derived from dietary purine compounds in normal man. These contribute to the increase in serum uric acid and renal excretion of uric acid according to the velocity of their enzymatic hydrolysis within the intestine and also according to their solubility and degree of absorption. 

Nugent and Tyler (1959) were the first to evaluate the influence of defined dietary purines on uric acid metabolism after specific methods for uric acid estimations had become available. They added different doses of ribonucleic acid (RNA) to a low-purine diet and found an increase in serum and urinary uric acid with increasing amounts of RNA. This soon became a standard method in studies of uric acid metabolism. A dose of 4 g RNA has been used by various authors to produce mild hyperuricemia in normal subjects (Table 2). 

Ref. (Dietary purine source) control purine supplementation control purine supplementation... 

We recently investigated the effect of oral purines on uric acid pool size and turnover rate in three normal subjects (Loffler et al., 1980a). The diet was an isoenergetic liquid formula diet free of purines and the purine supplement was 1 g AMP plus 1 g GMP per 70 kg body weight, which corresponds to about 4 g RNA as used by Powering et al. (1969). Results are shown in Table 3 and in Fig. 4. It is obvious that in normal subjects dietary purines lead to an increase in turnover rate of uric acid pool. 

Studies cited above have shown that renal uric acid clearance is enhanced to a lesser degree in gout than in normal humans when RNA is added to the diet. It can be concluded from this that, compared with controls, the turnover rate of the uric acid pool in familial gout is also increased less on dietary purine supplementation. 

Zollner, N., Griebsch, A. Influence of various dietary purines on uric acid production. In Urinary caculi. Proceedings of the International Symposium on Renal Stone Research. Madrid, 1972. S. Karger, Basel, 1973. 

The Contribution of Dietary Purines to Urinary Urate Excretion in Gouty and Renal Stone Patients... 

Hyperuricosuria is a major etiological factor in uric acid lithiasis. In addition, there is evidence for an etiological role of hyperuricosuria in calcium oxalate stone formation (1,2). Indeed, in our stone clinic, a high proportion of hyperuricosuria was also noticed among the patients with calcium urolithiasis. Since the hyperuricosuria in our stone clinic patients was established on the basis of urate determination on urine collections obtained on a regular home diet, the possibility of dietary hyperuricosuria was raised. We have therefore evaluated the contribution of dietary purine intake to uric acid excretion in our stone patients under controlled dietary conditions. 

The results of this study indicate that excessive purine intake is a major cause for hyperuricosuria among stone patients. Therefore, restriction of dietary purines is of therapeutic value in the treatment of nephrolithiasis. 

Coe, F.C., Moran, E. and Kavalach, A.G. The contribution of dietary purine over-consumption to hyperuricosuria in calcium oxalate stone formers. J. Chron. Disease, 29 793-800 (1976). 

The purine phosphoribosyltransferases permit cells to use exogenous or dietary purines, and this function is undoubtedly important to some bacteria and to those animal cells (e.g., erythrocytes) which do not synthesize purines de novo. The importance of this role in other animal cells in vivo is far from clear, however, as hypoxanthine is present in serum only at very low concentrations (50), and adenine and guanine have not been detected in normal serum. Purine bases (especially hypoxanthine and guanine) can be produced intracellularly by the catabolism of messenger RNA and soluble purine nucleotides their reutilization via the phosphoribosyltransferases would prevent the loss of these compounds from the cells. 

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