Purines, Urinary

Glycine participates in the biosynthesis of heme, purines, and creatine and is conjugated to bile acids and to the urinary metabolites of many drugs. 

Although demethylation, which occurs in the liver, is normally considered to be a catabolic process, it may result in conversion of an inactive form of a drug to the active form. Thus 6-(methylthio)purine (XXXIX) is demethylated by the rat to 6-mercaptopurine [205]. This demethylation occurs in the liver micro-somes and is an oxidative process which converts the methyl group to formaldehyde [204, 207]. The 1-methyl derivative of 4-aminopyrazolo[3,4-d] pyrimidine (XLI) is demethylated slowly, but 6-mercapto-9-methylpurine (XLII) not at all [208]. The A -demethylation of puromycin (XLlIl) [209, 210], its aminonucleoside (XLIV) [211], and a number of related compounds, including V-methyladenine and V,V-dimethyladenine, occurs in the liver microsomes of rodents [212]. In the guinea-pig the rate-limiting step in the metabolism of the aminonucleoside appears to be the demethylation of the monomethyl compound, which is the major urinary metabolite [213]. The relationship of lipid solubility to microsomal metabolism [214], and the induction of these demethylases in rats by pre-treatment with various drugs have been studied [215]. 

Urinary alkalinization- Urates tend to crystallize out of an acid urine therefore, a liberal fluid intake is recommended, as well as sufficient sodium bicarbonate (3 to 7.5 g/day) or potassium citrate (7.5 g/day) to maintain an alkaline urine continue alkalization until the serum uric acid level returns to normal limits and tophaceous deposits disappear. Thereafter, urinary alkalization and the restriction of purine-producing foods may be relaxed. 

Trimethoprim is a competitive inhibitor of the enzyme dihydrofolate reductase and can thus prevent the formation of tetrahydrofolate thereby blocking the synthesis of purines. The affinity of trimethoprim for the enzyme in microorganisms is 10,000 times higher than for the human enzyme which explains the selective toxicity. Used alone its main indication is acute uncomplicated urinary tract infections. It is then as effective as co-trimoxazole but has the advantage of fewer adverse reactions. 

Trimethoprim- sulfamethoxazole Synergistic combination of folate antagonists blocks purine production and nucleic acid synthesis Bactericidal activity against susceptible bacteria Urinary tract infections Pneumocystis jiroveci pneumonia toxoplasmosis nocardiosis Oral, IV renal clearance (half-life 8 h) dosed every 8-12 h t formulated in a 5 1 ratio of sulfamethoxazole to trimethoprim Toxicity Rash, fever, bone marrow suppression, hyperkalemia... 

Burnstock, G., Dumsday, B., Smythe, A. Atropine resistant excitation of the urinary bladder the possibility of transmission via nerves releasing a purine nucleotide, Br. J. Pharmacol. 1972a, 44, 451-461. 

In acute and chronic urinary tract infection, the combination of trimethoprim and sulfamethoxazole (Bactrim, Septra) exerts a truly synergistic effect on bacteria. The sulfonamide inhibits the utilization of p-amino-benzoic acid in the synthesis of folic acid (Figure 2.3), whereas trimethoprim, by inhibiting dihydrofolic acid reductase, blocks the conversion of dihydrofolic acid to tetrahydrofolic acid, which is essential to bacteria in the denovo synthesis of purines, pyrimidines, and certain amino acids. Because mammalian organisms do not synthesize folic acid and therefore need it as a vitamin in their daily diets, trimethoprim-sulfamethoxazole does not interfere with the metabolism of mammalian cells. 

Ldfroth, G., S. Osterman-Golkar, and R. Wennerberg. Urinary excretion of methylated purines following inhalation of dimethyl sulphate. Experientia 30 641-642, 1974. 

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. 

B. The DNA Funhouse. There is excess uric acid due to shunting through the HMP (Penthouse Powerhouse) shunt to form purines. Uric acid stones may deposit in the urinary tract. 

Normal serum uric add is 0.025 to O.OSO mg/ml in males and 0,015 to 0,060 mg/ml in females. A uric add level greater than 0 070 mg/ml is associated with an increased risk for gout- Purine-restricted diets can result in plasma uric add le cls of 0.005 to 0.015 mg/ml. About two-thirds of the uric acid in the body is excreted via the urine the rest is excreted in the feces. Uric add accounts for only about 5% of urinary nitrogen. 

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,... 

Clifford, A, ], Rlumallo, J. A., Young, V R and Scrimshaw, N. S- (1976). Effect of oral purines on serum and urinary uric acid of normal, hyperurkemic and gouty humans. /. Nw(r 106, 426-450. 

E. Dudley, F. Lemiere, W. Van Dongen, R. Tuytten, S. El-Sharkawi, A.G. Brenton, E.L. Esmans, R.P. Newton, Analysis of urinary nucleosides. IV. Identification of urinary purine nucleosides by LC-ESI-MS, Rapid Commun. Mass Spectrom., 18... 

However, creatinine and purine derivatives are very important in the field of animal nutrition because measurements of urinary excretion of these compounds have been proposed as an internal marker for microbial protein synthesis. 

Several HPLC methods have been reported for the determination of xanthine and hypoxanthine. Different RP-HPLC methods, using gradient elution and UV detection, have been described to determine these metabolites and other methylated purines.To improve xanthine determination in urine samples, analyses were carried out with two columns—reversed-phase column and anion exchange column—connected by a column switch. With this method, urinary hypoxanthine and xanthine can be measured without any sample preparation other than filtration. ... 

Di Pietro, M.C. Vannoni, D. Leoncini, R. Liso, G. Guerranti, R. MarineUo, E. Determination of urinary methylated purine pattern hy high-performance liquid chromatography. J. Chromatogr., B 2001, 751, 87-92. 

Safranow, K. Zygmunt, M. Ciechanowski, K. Analysis of purines in urinary calcuh hy high-performance liquid chromatography. Anal. Biochem. 2000, 286, 224-230. 

Purines are metabolized in a series of reactions involving hypoxanthine, xanthine, uric acid, and allantoin as end products that are subsequently excreted in urine. Fig. 3 shows the metabolic pathways for xanthine. Measurement of urinary excretion of purine metabolites, primarily allantoin or, additionally, uric acid, xanthine, and hypoxanthine, has been proposed as a marker for microbial... 

In practice, the majority of TLC separations are qualitative or semiquantitative (visual comparison) in nature. However, modern computer-controlled densitometers are now available that scan sample and calibrator chromatograms in tracks on HPTLC plates and provide quantitative capabilities. Clinically relevant analytes that have been measured by TLC include amino acids, bile acids, carbohydrates, drugs, fipids, glycolipids, phospholipids, porphyrins, prostaglandins, steroid hormones, purines, pyrimidines, derivatives of nucleic acid, and urinary organic acids. The advantages of TLC include simphcity, rapidity, versatility, ability to process a large number of samples... 

Kidney Stones. About one in five patients with clinical gout also has urinary tract uric acid stones. Although plasma and urinary uric acid should he measured in stone formers, many uric acid stone formers do not demonstrate either hyperuricuria or hyperuricemia. However, this may reflect the use of reference intervals derived in a purine-rich, westernized society.The etiology of uric acid stone formation also involves the passage of a persistently acid urine with loss... 

Urinary uric add excretion in individuals on a diet containing purines is 250 to 750mg/day (1.5 to 4.5mmol/day). Excretion may decrease by 20% to 25% on a purine-free diet to less than 400 mg/day. 

Carriers of OCT deficiency (estimated to be several thousand women in the U.S. A.) can be identified by administration of a single oral dose of allopurinol, a purine analogue, followed by measurement of urinary orotidine excretion. The underlying principle of this assay is that when the intramitochondrial carbamoyl phosphate accumulates in OCT heterozygotes, it diffuses into the cytoplasm stimulating the biosynthesis of pyrimidines. One of the intermediates in this pathway—orotidine—accumulates, leading to orotidinuria (Figure 17-8). 

The serum uric acid pool and the amount of uric acid excreted are dependent upon many physiological factors. One of the more obvious of these is kidney function. About 60 years ago, Leathes (L5) noted that during work there was a decrease in urinary uric acid excretion coupled with an apparent increase in excretion of other purine bases. He felt that... 

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