Allopurinol guanine

Treatment the drug that most effectively inhibits the formation of uric acid is allopurinol, a competitive inhibitor of xanthine oxidase. Hypoxanthine and xanthine are excreted during allopurinol therapy. Allopurinol, as with guanine and hypoxanthine, can be converted to its ribonucleotide form by HGPRT. Reducing the formation of uric acid with allopurinol relieves the symptoms of gout and decreases the possibility that uric acid kidney stones will form. 

Xanthine nephropathy has been reported in tumor lysis syndrome (TLS) in patients with hypoxanthine-guanine phosphoribosyl transferase (HGPRT) enzyme deficiency [180b], however, this patients cultured fibroblasts yielded normal levels of HGPRT enzyme. Allopurinol pretreatment allows the build up of both xanthine and hypoxanthine which, in the absence of HGPRT, cannot be recycled and thus xanthine supersaturation in the urine resulting in xanthine stones with subsequent obstructive renal failure. 

MeX,hypoX,X,DA,adenine, guanine,allopurinol Analysis in biological fluids Hypersil ODS 3 pm 150x4.6 0.02M KH2P04(pH 3.65) 198... 

Recently it has been shown that patients with this disease excrete more hypoxanthine than xanthine in their urine. All other subjects studied excrete more xanthine than hypoxanthine (B7). Furthermore, although the administration of allopurinol reduces total oxypurine output in other patients, it does not do so in these children (B7, 02). These observations have been clarified by the demonstration that patients with juvenile hyperuricemia lack inosinate pyrophosphorylase, the enzyme that catalyses the conversion of hypoxanthine (and guanine) to inosinic acid (and guanylic acid) (SlOa). They, thus, excrete any hypoxanthine formed rather than reutilize it. This may identify the fundamental difference between this entity and gout, but offers no explanation of the neurological damage. 

The answer is d. (Murray, pp 375-401. Scriver, pp 2513-2570. Sack, pp 121-138. Wilson, pp 287-320.) Xanthine oxidase catalyzes the last two steps in the degradation of purines. Hypoxanthine is oxidized to xanthine, and xanthine is further oxidized to uric acid. Thus, xanthine is both product and substrate in this two-step reaction. In humans, uric acid is excreted via the urine. Allopurinol, an analogue of xanthine, is used in gout to block uric acid production and deposition of uric acid crystals in the kidneys and joints. It acts as a suicide inhibitor of xanthine oxidase after it is converted to alloxanthine. Guanine can also be a precursor of xanthine. 

There are three distinct PRTases in L. donovani (30). One has its major activity with hypoxanthine and guanine a second with adenine and a third with xanthine. Pyrazolo (3,4-d)pyrimidines, such as allopurinol, are efficient substrates for the HGPRtase. Promastigotes accumulate large quantities of allopurinol ribonucleoside-5 -phosphate when exposed to allopurinol (31). A separate PRTase for xanthine is unusual in a eukaryotic cell. XPRTase is also present in L. mexicana and L. amazonensis as well as in four non-pathogenic trypanosomatids (32,33). 

Few detailed studies have been done on the purine salvage enzymes of procyclic African trypanosomes. Tb. gambiense has high levels of guanine deaminase and lacks adenine and adenosine deaminase activities (8). Tb. brucei, T.b. gambiense and T.b. rhodesiense convert allopurinol into aminopyrazolopyrimidine nucleotides and incorporates these into RNA (49). This indicates that HPRTase, succino-AMP synthetase, and succino-AMP lyase are present. At least three nucleoside cleavage activities are present (Berens, unpublished results) two are hydrolases, of which one is specific for purine ribonucleosides and the other is specific for purine deoxyribonucleosides. The third nucleoside cleavage activity is a methylthioadenosine/adenosine phosphorylase. The adenosine kinase is similar to that of L. donovani (Berens, unpublished results). 

The biosynthesis of uric acid from the immediate purine precursor xanthine that results from adenine, via the intermediate hypoxanthine, or from guanine is illustrated in Figure 36.32. The enzyme xanthine oxidase (a molybdenum hydroxylase enzyme) is involved in two steps, the conversion of hypoxanthine to xanthine, and the final step, the conversion of xanthine to uric acid. Allopurinol originally was designed... 

Simmonds, H. A., Hatfield, P. J., Cameron, J.St. Metabolic studies of purine metabolism in the pig during the oral administration of guanine and allopurinol. Biochem. Pharmacol. 22 2537 (1973). 

Both ribose-l-P and deoxyribose-l-P serve as sugar donors in the synthetic reaction. In addition to the naturally occurring purines, certain purine analogues can also serve as substrates or inhibitors of purine nucleoside phosphoiylase. Of these, 8-azaguanine, 6-mercaptopurine, 6-thio-guanine, and allopurinol bind most tightly to the human erythrocyte enzyme 17). 

Pigs were given a large purine load (guanine 150mg/kg/day) or a xanthine oxidase inhibitor (allopurinol 300mg/kg/day). 

Effect of dosing pigs with allopurinol (300mg/kg) and guanine (150mg/kg) for 3 weeks, on blood urea levels. 

Feeding large quantities of guanine or allopurinol separately did not produce any histological changes, but when administered together, crystalline deposits were found in the kidneys, which were shown to consist of xanthine and oxypurinol. The position of the crystals in the distal tubules suggests that their formation at that site was due to concentration of urine. 

Cross section of whole kidney showing widespread fibrous tissue, principally involving the medullary rays. Kidney from pig dosed for 21 days, allopurinol, 300mg/kg and guanine (150mg/kg, then allowed 28 days recovery period. 

Fig. 4. Metabolism of allopurinol and oxipurinol to ribonucleotides that act as inhibitors of orotidylic decarboxylase. OPRT = orotate phosphoribosyltransferase HGPRT = hypoxanthine-guanine phospho-ribosyltransferase.

Fig. 5. The effect of allopurinol therapy on erythrocyte orotidylic decarboxylase (ODC), orotate phosphoribosyltransferase (OPRT), hypoxanthine-guanine phosphoribosyltransferase (HGPRT), and adenine phosphoribosyltransferase (APRT), and serum urate in three patients with gout. The upper limits of normal OPRT and ODC activity in erythrocytes (mean 2 S.D.) are indicated by the dotted and solid horizontal lines, respectively. (From Beardmore, Cashman and Kelley, 1972).

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) ... 

The combination of guanine and allopurinol produced an acute crystal nephropathy in the pig and permanent renal damage ( ). 

In this paper we present results of experiments in which we have investigated the effect of allopurinol in the pig, firstly on a low purine diet and then given an oral purine supplement in the form of guanine (3) ... 

When dietary guanine was supplemented with allopurinol the excretion patterns changed considerably, only of the radioactivity being excreted in the urine, the remainder being... 

Similar experiments using intravenous C guanine have been carried out to determine whether allopurinol produces this effect by blocking absorption or enhancing purine excretion into the gut. In these experiments 13% of the intravenously administered label was excreted into the gut during allopurinol therapy, and less than 1% was found in the faeces when guanine was given alone. However, respiratory C02 was measured for only the first t onty-four hours in these experiments, and these results therefore require to be substantiated. 

---