Orotidine urinary excretion

There are several studies on the effect of allopurinol and its metabolic derivatives on orotate phosphoribosyltransferase and orotidylic acid decarboxylase [127-129]. The administration of allopurinol to rats results in an increased urinary excretion of orotic acid and orotidine [127,130,131], and in elevated activities of orotate phosphoribosyltransferase and orotidylic acid decarboxylase in erythrocytes [128,129]. Also, in man, the administration of allopurinol and oxipurinol leads to an increase in the specific activity of orotate phosphoribosyltransferase and orotidylic acid decarboxylase [129]. The enzymes were found to exist in a complex as three different molecular species with molecular weights of 55000, 80000 and 113 000 daltons. The larger forms of the complex were more stable than the smaller one. In the presence of allopurinol or oxipurinol ribonucleotides (but not the corresponding free bases) the largest, most stable species predominated [129]. 

In cells, azauridine is converted to the 5 -monophosphate, which is a competitive inhibitor of orotidylate decarboxylase. Orotidylate accumulates because of the inhibited enzyme and its subsequent degradation explains the urinary excretion of orotidine in azauridine-treated animals. Azauridine has been used to treat acute leukemia in man, but resistance to the drug develops rapidly. 

Weissmann et al. (4) have calculated that in man approximately 800 to 1000 mg of uracil are synthesized de novo per day. The normal urinary excretion of orotate is approximately 1.4 mg per day, and that of orotidine, 2.5 mg per day (6). In patients with orotic aciduria due to decreased orotidylate decarboxylase, the excretion of orotate may increase 20-fold (5), although the excretion of orotidine does not necessarily increase. 

The number of inherited defects of the pyrimidine metabolism described so far is small, compared to that of the purine metabolism. Combined deficiency of orotate phosphoribosyltransferase (OPRT) (EC 2.4.2.10) and orotidine 5 -monophosphate decarboxylase (ODC) (EC 4.1.1.23), designated as type I hereditary orotic aciduria, presents with characteristic clinical features such as hypochromic anemia with a megaloblastic bone marrow and crystalluria. Only six patients have been described and, as far as we know, new cases have not been discovered recently. ODC deficiency with similar clinical phenomena and leading to increased urinary excretion of orotate and orotidine has been detected in only one patient (1). A third defect, a deficiency of pyrimidine 5 -nucleotidase (Py-5NX (EC 3.1.3.5.) in erythrocytes, is associated with chronic hemolytic anemia and prominent basophylic stippling of the erythrocytes due to accumulated pyrimidine nucleotides. An increasing number of patients have been reported, their detection being facilitated by the typical phenomena. We do not know whether the urinary pyrimidine profile in this condition is abnormal. 

J.W. Stoop and S.K. Wadman, Urinary excretion of orotic acid, orotidine and other pyrimidines in a patient with purine nucleoside phosphorylase deficiency, Clin. Chim. Acta, 93 ... 

Table 3. Reduction of urinary excretion of orotic acid and orotidine by dietary purines.

The resultant clinical state is characterized by failure of growth and development, megaloblastic anemia, and the increased urinary excretion of orotic acid (Types I and II) and orotidine (Type II). 

When guanine was given together with the allopurinol, the increased urinary excretion of orotic acid and orotidine remained unchanged at 50 mg/2 hours. This is in contrast to the findings in man, where exogenous RNA fed together with allopurinol eliminated the increase in excretion of orotic acid and orotidine (3) ... 

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). 

Pigs given allopurinol showed an increase in urinary orotic acid and orotidine excretion from a mean of 5 to a mean of 50 mg/2 hours. Although the dose of allopurinol was constant the levels of orotic acid and orotidine fell gradually from their initial peak. When the drug was stopped levels returned rapidly to normal. These results are similar to those obtained in rat and man (I), where this effect has been attributed to inhibition of the enzyme orotidylic decarboxylase (2). 

As renal function deteriorated there was a proportional increase in urinary levels of orotic acid and orotidine. This increased excretion would appear to be related to the increase in plasma oxipurinol levels which have been reported in renal failure (5) ... 

Oxonic acid is a uricase inhibitor (6) and has been given to rodents to produce an animal model for gout (7). When given to pigs urinary allantoin excretion decreased, as uric acid excretion increased. These findings indicate inhibition of the enzyme uricase. However, oxonic acid also produced a great increase in orotic acid and orotidine excretion. Urinary levels increased from 5 nig to 900 mg/2A hours, and this would imply a complete or... 

Elevated concentrations of orotic acid and uracil may be found in the urine of heterozygote carriers for urea cycle disorders, most commonly ornithine carbamoyltransferase (OCT) deficiency. This is due to the increased flux through the pyrimidine pathway which occurs, especially where the relevant enzymes are expressed only in liver tissue, as is the case when urea cycle enzymes are defective. A protein load was used previously to stress this route and the elevation in orotic acid excretion used as a diagnostic marker. However, the test frequently failed to detect known carriers. The al-lopurinol loading test (measurement of the increment in urinary orotic acid and orotidine in three separate 8 hour urine collections over the 24 hours following a 300 mg allopurinol tablet) is the most reliable test so far for carrier detection for such disorders [17]. 

Urinary pyrimidines and uric acid. Administration of PF was followed by the excretion of a large amount of orotic acid and orotidine. Fig. 2 shows the total ion chromatogram of the urine of a patient 2 days after PF infusion started (250 mg/m ). The peaks corresponding to mass spectrayA 230 and 258 on the abscissa are hippuric and citric acid, respectively. In the control urine... 

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