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. 

Gout is caused by an abnormality in uric acid metabolism. Uric acid is a waste product of the breakdown of purines contained in the DNA of degraded body cells and dietary protein. Uric acid is water soluble and excreted primarily by the kidneys, although some is broken down by colonic bacteria and excreted via the gastrointestinal tract. 

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. 

A. Salvage pathways allow synthesis of nucleotides from free purines or pyrimidines that arise from nucleic acid degradation or dietary sources, which is more economical for the cell than de novo synthesis. 

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. 

Uric acid production is more easily controlled by drug therapy than by dietary restriction, because only a small portion of blood uric acid is derived from the dietary intake of purines. Excretion of uric acid may be increased by increasing the rate of urine flow or by using uricosuric agents. Since uric acid is filtered at the glomerulus and both actively secreted and reabsorbed by the proximal tubule cells, both approaches are effective. 

C. The dietary intake of purines is not a major contributing factor to uric acid blood levels. Therefore, pharmacological reduction of uric acid synthesis or increased excretion is required. Dietary restriction (A) can affect uric acid production if precursor molecules are lowered sufficiently, but this usually is not feasible. The question of drug specificity (B) is not germane to the question. Pathways of uric acid synthesis in the body (D) are well known. 

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. 

Concentrations of metabolites outside the reference ranges may constitute a typical pattern indicating the presence of an inborn error of purine or pyrimidine metabolism. However, altered excretions of purine and pyrimidines may also be a secondary phenomenon due to the presence of other metabolic disorders, such as a deficiency of the urea cycle [15]. Increased concentration of a single metabolite or combinations of metabolites may also result from bacterial contamination, sample conditions, medication, or dietary compounds [6]. 

Degradation of dietary nucleic acids occurs in the small intestine, where a family of pancreatic enzymes hydrolyzes the nucleotides to nucleosides and free bases. Inside cells, purine nucleotides are sequentially degraded by specific enzymes, with uric acid as the end product of this pathway. [Note Mammals other than primates oxidize uric acid further to allantoin, which, in some animals other than mammals, may be further degraded to urea or ammonia.]... 

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. 

Finally, purines such as caffeine (including dietary caffeine in coffee, tea, colas, and chocolate) and synthetic derivatives, such as theophylline, can interfere with the vascular actions of dipyridamole, These agents act to inhibit the adenosine A2A receptor, which serves to further emphasize the role of adenosine in the pharmacologic actions of dipyridamole (41-43), It has also been shown that this effect on A2A receptors is restricted to the vessel wall the direct anti-aggregatory actions of dipyridamole are not blocked by purines and may, if anything, be enhanced by the indirect effect of purines to upregulate A2A receptors (44,45). 

The so-called salvage pathways are available in many cells to scavenge free purine and pyrimidine bases, nucleosides, and mononucleotides and to convert these to metabolically useful di- and trinucleotides. The function of these pathways is to avoid the costly (energy) and lengthy de novo purine and pyrimidine biosynthetic processes. In some cells, in fact, the salvage pathways yield a greater quantity of nucleotides than the de novo pathways. The substrates for salvage reactions may come from dietary sources or from normal nucleic acid turnover processes. 

In addition to being synthesized or produced by the hydrolysis of dietary protein, amino acids can come from hydrolysis of tissue proteins, e.g., intestinal mucosa or, during starvation, muscle. Amino acids are used in protein synthesis (Chap. 17) they also enter gluconeogenesis and lipogenesis are degraded to provide energy and are used for synthesizing compounds such as purines, pyrimidines, porphyrins, epinephrine and creatine. 

The general scheme for the degradation of nucleic acids has much in common with that of proteins. Nucleotides are produced by hydrolysis of both dietary and endogenous nucleic acids. The endogenous (cellular) polynucleotides are broken down in lysosomes. DNA is not normally turned over rapidly, except after cell death and during DNA repair. RNA is turned over in much the same way as protein. The enzymes involved are the nucleases deoxyribonucleases and ribonucleases hydrolyze DNA and RNA, respectively, to oligonucleotides which can be further hydrolyzed (Fig. 15-18), so eventually purines and pyrimidines are formed. 

Possible risk factors include trauma, unusual physical exercise, surgery, severe systemic illness, severe dieting, dietary excess, alcohol, drugs, status epilepticus, psoriasis, renal failure, lead intoxication, Down s syndrome, high purine diet, cytolytic therapy, myeloproliferative and lymphoproliferative disorders. Mr KT has several risk factors which increase his chances of developing gout ... 

Levels of 8-OHdG have also been measured in human and rodent urine. Preliminary results indicate a trend towards lower levels in CGD patients than in normal control subjects [141], It is also reported that urinary 8-OHdG levels are higher in mice than in humans [142]. However, it is not known whether this product in human urine is derived exclusively from DNA via repair-enzyme processes Oxidation of free guanine, normal purine metabolism and/or dietary factors might contribute to urinary 8-OHdG. 

The enzyme dihydrofolic acid (DHF) S5mthase (see below) converts p-aminobenzoic acid (PABA) to DHF which is subsequently converted to tetrahydric folic acid (THF), purines and DNA. The sulphonamides are structurally similar to PABA, successfully compete with it for DHF s)mthase and thus ultimately impair DNA formation. Most bacteria do not use preformed folate, but humans derive DHF from dietary folate which protects their cells from the metabolic effect of sulphonamides. Trimethoprim acts at the subsequent step by inhibiting DHF reductase, which converts DHF to THF. The drug is relatively safe because bacterial DHF reductase is much more sensitive to trimethoprim than is the human form of the enzyme. Both sulphonamides and trimethoprim are bacteriostatic. 

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. 

The following study demonstrates the effect of dietary protein on uric acid. In the study, human subjects consumed diets containing no protein, normal levels of protein, and extremely high levels of protein. The diets were chemically defined and did not contain purines. The protein-free diet supplied 0.9 g N/day. The normal-protein diet supplied 13 g l>J/day, The extremely high-protein diet supplied 62 g N/day. The feeding trials were 2 weeks in duration. The norma I-protein diet contained 90 g of egg albumin, which was supplemented with 162 g of soy protein plus 156 g of casein in the high-protein diet. 

Studies by CJifford ft /if. 197ft) revealed the effect of purine consumption on uric acid levels. The purines were supplied to human subjects in the form of ribonucleic acid (RNA) 4g/day). Purine consumption resulted in a near doubling of plasma levels of uric acid and a 2.5-fold increase in urinary uric acid, Thi.s demonstrates the need for avoiding purine rich foods in treating hyperuricemia and gout, it has been recommended that the maximal safe limit of RMA in the diet is 2,0 g/day (Clifford ef ai, 1976). 1)115 amount of RNA can be supplied by 340 g cf sardines, 415 g of dried lentils or pinto beans, or 500 g of chicken liver. As few people consume, or would be willing to consume, 500 g of liver per day the limitation of dietary RNA to safe levels would not be expected to be a common concern,... 

---