Xanthine urinary excretion

Gout is caused by the deposition of crystals of monosodium urate hydrate which are ingested by leucocyctes and trigger the inflammatory response. The biosynthesis of uric acid involves the oxidation of the more soluble compound xanthine (2,6-dihydroxypurine) by xanthine oxidase, and this enzyme is inhibited by allopurinol (187). The treatment of gout also relies on uricosuric drugs to accelerate urinary excretion of uric acid and antiinflammatory drugs to ease the pain and inflammation. 

The nucleoside formed from hypoxanthine and ribose is known as inosine (Ino or I) and the corresponding nucleotide as inosinic acid. Further substitution at C-2 of -H by -OH and tautomerization yields xanthine (Xan). Its nucleoside is xanthosine (Xao, X). A similar hydroxylation at C-7 converts xanthine to uric acid, an important human urinary excretion product derived from nucleic acid bases. 

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... 

This autosomal recessive trait results in hypouricemia and in increased urinary excretion of hypoxanthine and xanthine. Patients frequently have xanthine stones. 

Using tungsten as a molybdenum antagonist, Higgins etal. (1956) demonstrated a 95-97% loss in rat intestine and liver xanthine oxidase activity, but without any notable adverse effect on the animals. However, in chicks - which use uric acid as the primary route of nitrogen excretion - oral administration of tungsten decreased urinary excretion of uric acid and caused a rise in fecal xanthine and hypoxanthine output, a reduction in growth, and an increase in mortality. 

Creatinine and purine derivatives—allantoin, uric acid, hypoxanthine, and xanthine present in biological samples— are important analytes for diagnoses of certain types of metabolic diseases and can serve as markers for these processes. Analyses for such substances are cmcial for diagnosis and the monitoring of renal diseases, metabolic disorders, and various types of tumorigenic activity. On the contrary, these compounds are very important in the field of animal nutrition, because the measurement of their urinary excretion is being used as an internal marker for microbial protein synthesis. 

Uric acid and xanthines are markers for metabolic disorders such as gout, Lesch—Nyman syndrome, and xanthinuria. Measurements of urinary excretion of purine metabolites, among them uric acid and xanthine, have been proposed as a marker for microbial protein synthesis. Their simultaneous determination is useful for diagnosis and treatment of hyperuricemia. In addition to xanthine and hypoxanthine, notable members of the xanthine class include caffeine, theophylhne, and theobromine. ... 

Urinary uric acid, hypoxanthine, xanthine, allopurinol excretion assay by HPLC... 

In vivo xanthine oxidase inhibition results in a reduction of uric acid (and allantoin) in urine and in an increase in the urinary excretion of hypoxanthine and xanthine as described by Elion 1 for allopurinol. The dose-dependence of the excreted amounts of hypoxanthine and xanthine is a relevant consideration when using these parameters to measure the action of uricostatics in the rat. The purpose of our studies was to obtain a simple and rapid method to detect the uricostatic quality of hypouricemic compounds. 

Fig.1 Urinary output of uric acid, hypoxanthine+xanthine, uracil and CAMP in 18 normal newborns on their first and fourth day of life. Mean and SD-range of the values. The 24-h. urinary excretions of the same substances measured in 4 newborns during and after E.T. are plotted. Numbers above the circles refer to the patient s number.

Manzke, H., Spreter v. Kreudenstein, P., Dorner, K., and Kruse, K., 1980, Quantitative measurements of the urinary excretion of creatinine, uric acid, hypoxanthine and xanthine, uracil, cyclic AMP and cyclic GMP in healthy newborn infants, Eur. J.Pediatr. 133 157... 

Although his pre-treatment plasma uric acid level was only modestly elevated (7 3 mg/100 ml.) his urinary excretion was 1,140 mg in 2k hours His creatinine clearance was 155 mg/min He had been satisfactorily treated with Allopurinol which was stopped one month prior to the commencement of the present study. With kOO mg of thiopurinol per day the plasma uric acid fell in one week from 7 2 to 5 0 mg/100 ml., a drop of 315 . At the same time the urinary uric acid excretion fell by 52%, with no change in the urinary excretion of xanthine or hypo-xanthine or in their ratio ... 

At the present time, we just report some experimental results of a study on the mechanism of action of allopurinol (U-hydroxy-pyrazolo (3, -d ) pyrimidine) and thiopurinol k thiopyrazolo (3, d) pyrimidine) on de novo biosynthesis of uric acid. In this present work, we have compared effect of alio and thiopurinol on oxypurine (xanthine and hypoxanthine) urinary excretion with their rate of synthesis of ribonucleotides in vitro by erythrocyte hemolysate in some particular enzymatic deficiencies (hypoxanthine-guanine phosphoribosyltransferase HGPRT, adenine phosphoribosyl-transferase APRT and xanthinuria). 

Xanthinuria is characterized by a large urinary excretion of oxypurine (xanthine + hypoxanthine) which replaces uric acid at the end product of purine metabolism. Patients with xanthinuria are very deficient in xanthine oxidase activity. This rare metabolic disorder may be of interest for both information ... 

We have given allopurinol and thiopurinol to a xanthinuric man and in this communication we report on the urinary excretion amount of U-6 dihydroxy PP oxipurinol, or i+-thio-6-hydroxy PP oxithiopurinol and the concomitant values of xanthine and hypoxanthine. 

The clinical case of this xanthinuric man has been reported by DELBARRE in a previous paper (to be published). This man is a pastry cook since he could not be in the hospital more than one or two days, most determinations were done without control diet. This explains the great difference of daily urinary oxypurine values that were found. This patient has normal renal function (creatinine clearance = 99 ml/min). His averaged uric acid and oxypurines (xanthine and hypoxanthine) plasma concentration were 1.2 and 0.58 mg per 100 ml. His 95 % range ( mean + 2s) urinary excretion of uric acid is 7 to 27 mg per day and of oxypurine 310 to 618 mg... 

His urinary excretion was normal for adenine (1,73 mg/ day) and for guanine (0,93 mg/day). We dit not find any measurable amount of 8 hydroxy-7 methyl guanine in daily urine but a concomitant increase of 7"methyl guanine (9 10 mg/day control 6,9 mg/day). SKUPP and AYVAZIAN (1969) have demonstrated that 8 hydroxy-7 methyl guanine is the product of oxidation ofT-methyl guanine but only by human liver xanthine oxidase. This xanthinuric man has a family, but up to now we have only seen one of his sisters who also has xanthinuria. 

We have found no modification of urinary excretion amount of oxypurines or of the ratio of hypoxanthine to xanthine after 3,7 and 57 days allopurinol (200 mg/days) and 3,5,1 and 25 days of thiopurinol(500 mg/days) administration, nor during the 2h hours following administration of a single dose of every PP. All the values found were in the 95 % range limits of the mean values obtained without treatment. 

Xanthine oxidase does not act on biopterin (Forrest et al., 1956). The pattern of urinary excretion of biopterin might be expected, therefore, to differ not only from that of xanthopterin, but also from uric acid. The excretion of uric acid is elevated in leukemia, perhaps reflecting (Krakoff, 1957) an acceleration of nucleic acid ssmthesis. If this acceleration entailed parallel increases in the folic acid and other cofactors for making nucleic acid, then it would account for the increased excretion of xanthopterin in leukemia noted earlier. The turnover of biopterin in leukemia and in normal subjects is, one must emphasize, entirely unknown. 

The urinary excretion data of uric acid and oxypurine in conjunction with the extremely low serum urate speak strongly for this. However, we have not measured the xanthine oxidase levels in the tissue of these patients leaving some small measure of doubt as to the true etiology of these deranged values. 

From metabolic studies, an isotopic caffeine breath test has been developed that detects impaired liver function using the quantitative formation of labeled carbon dioxide as an index. From the urinary excretion of an acetylated uracil metabolite, human acet-ylator phenotype can be easily identified and the analysis of the ratio of the urinary concentrations of other metabolites represents a sensitive test to determine the hepatic enzymatic activities of xanthine oxidase and microsomal 3-methyl demethylation, 7-methyl demethylation, and 8-hydroxylation. Quantitative analyses of paraxanthine urinary metabolites may be used as a biomarker of caffeine intake. Fecal excretion is a minor elimination route, with recovery of only 2-5% of the ingested dose. 

Allopurinol, in contrast to the uricosuric drugs, reduces serum urate levels through a competitive inhibition of uric acid synthesis rather than by impairing renal urate reabsorption. This action is accomplished by inhibiting xanthine oxidase, the enzyme involved in the metabolism of hypoxanthine and xanthine to uric acid. After enzyme inhibition, the urinary and blood concentrations of uric acid are greatly reduced and there is a simultaneous increase in the excretion of the more soluble uric acid precursors, xanthine and hypoxanthine. 

Since allopurinol blocks xanthine conversion to uric acid, urinary xanthine excretion is increased, creating a risk of xanthine crystal formation in the urinary system or even in muscles this can result in nephrolithiasis (12). It is still an open question whether a predisposition to renal disease or renal disease itself is required to precipitate these adverse effects. It is also not known whether increased excretion of orotic acid, due to an interaction of allopurinol with pyrimidine formation, has any consequences for these adverse effects or for its role in reducing glucose tolerance. 

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