Purine metabolism, effect

The subject of the incorporation of anticancer agents into macromolecules [13] and other compounds [336] has been reviewed. A number of purine analogues are incorporated into nucleic acid, but the incorporation of these compounds requires that they be anabolized to nucleoside mono-, di-, and triphosphates, and it is difficult to separate the metabolic effects of the nucleoside phosphates from the metabolic effects of the fraudulent polynucleotides. 

Azaguanine was the first purine analogue shown to be incorporated into polynucleotides [337] and, since its primary metabolic effect is on protein synthesis, the incorporation into RNA is considered the basis for its biologic activity [338]. In microbial systems 8-aza-adenine, 8-azahypoxanthine, 8-azaxanthine, and 5(4)-amino-l/f-l, 2, 3-triazole-4(5)-carboxamide are all incorporated into RNA as 8-azaguanylic acid [336]. 

Another signihcant feature of the proximal tubule is that it is the site of organic acid transport. This is important in understanding both the pharmacokinetics of many of the diuretics, most of which are weak organic acids, and also certain of the side effects induced by these drugs. For instance, uric acid, which is the end product of purine metabolism in humans, is both reabsorbed and secreted by the organic acid transport pathway (see Chapter 37). 

Mechanism of Action An immunologic agent that antagonizes purine metabolism and inhibits DNA, protein, and RNA synthesis. Therapeutic Effect Suppresses cell-mediated hypersensitivities alters antibody production and immune response in transplant recipients reduces the severity of arthritis symptoms. 

Azathioprine is a cytotoxic inhibitor of purine synthesis effective for the control of tissue rejection in organ transplantation. It is also used in the treatment of autoimmune diseases. Its biologically active metabolite, mercaptopurine, is an inhibitor of DNA synthesis. Mercaptopurine undergoes further metabolism to the active antitumour and immunosuppressive thioinosinic acid. This inhibits the conversion of purines to the corresponding phosphoribosyl-5 phosphates and hypoxanthine to inosinic acid, leading to inhibition of cell division and this is the mechanism of the immunosuppression by azathioprine and mercaptopurine. Humans are more sensitive than other species to the toxic effects of the thiopurines, in particular those involving the haematopoietic system. The major limiting toxicity of the thiopurines is bone marrow suppression, with leucopenia and thrombocytopenia. Liver toxicity is another common toxic effect. 

Antimetabolites selectively compete for intermediary metabolites critical to immime cell function, exerting a cytotoxic effect. Methotrexate (Folex ), which inhibits folic acid, is the most widely recognized and used drug in this class. Other antimetabolites that may be used in treating uveitis include azathioprine (Imuran ) and mycophe-nolate mofetil (CellCept ), both of which interfere with purine metabolism. 

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. 

The metabolic effects of epinephrine are important during injury. Epinephrine can activate purine metabolism and may contribute to the increased excretion of nitrogen after injury (G9). Epinephrine and norepinephrine promote chemical thermogenesis after injury and thus will contribute to the increased metabolic expenditure of the injury period (S7). Epinephrine will also cause an acute lowering of the plasma albumin with a rise in the a-globulin fraction probably due to the effect on ACTH secretion. 

Adrenaline at a dose of 80 fig can activate purine metabolism and markedly increase total nitrogen excretion in rats. This action is not blocked by ergot alkaloids, and the opposite effect is produced by acetylcholine (G17, G18). 

Thioguanine has multiple metabolic effects. Its tumor inhibitory properties may be due to one or more of its effects on feedback inhibition of de novo purine synthesis inhibition of purine nucleotide interconversions or incorporation into DNA and RNA. The net conseqnence of its actions is a sequential blockade of the synthesis and utilization of the purine nucleotides. 

Mechanism of action This prodrug is transformed to the anti metabolite mercaptopurine, which upon further metabolic conversion inhibits enzymes involved in purine metabolism. Azathioprine is cytotoxic in the early phase of lymphoid cell proliferation and has a greater effect on the activity of T cells than B cells. 

Allopurinol, a xanthine oxidase inhibitor used for the treatment of gout, inhibits metabolism of 6-mercaptopurine and other drugs metabolized by this enzyme. A serious drug interaction results from the concurrent use of allopurinol for gout and 6-mercaptopurine to block the immune response from a tissue transplant or as antimetabolite in neoplastic diseases. In some cases, however, allopurinol is used in conjunction with 6-mercaptopurine to control the increase in uric acid elimination from 6-mercaptopurine metabolism. The patient should be supervised closely, because when given in large doses, allopurinol, an inhibitor of purine metabolism, may have serious effects on bone marrow. 

Occurrence In small amounts in muscles, liver, urinary calculi, beet juice, barley shoots, fly agarics, peanut kernels, potatoes, yeasts, coffee beans, tea leaves. X. is formed in the metabolism of higher animals by deamination of guanine (component of nucleic acid) or oxidation of hypoxanthine by xanthine oxidase present in muscles which then also oxidizes X. further to uric acid, the final product of the purine metabolism in humans. The nucleoside derived from X. is xanthosine. Although X. is chemically closely related to "caffein(e) and other methylxanthines, its activity is different. Stimulation of the central nervous system is less pronounced, the paralyzing effects dominate, and cardiac muscles are severely damaged. 

As hy pox an thine is an end product of purine metabolism in tissues lacking xanthine oxidase, we investigated the concentration of hypoxanthine in meat, and compared this with the effects seen after oral administration of hypoxanthine (Spann et al., 1980). The hypoxanthine content of pork increased with time of storage and with temperature. The nutrition experiment showed that the content of 200 g of barely edible pork resulted in an increase in serum uric acid of only 0.15 mg/100 ml. This was less than the increase produced by RNA. 

Erythrocyte HGPRT levels were maintained at 15 to 70% of normal enzyme activity (72 mnol/hr mg prot). The effect of the transfusions on purine metabolism was monitored by serum urate, urinary purines and CSF oxypurine values (Table 2). 

Table 2. Effect of Transfusion Therapy on Purine Metabolism...

---