Bone marrow, purine metabolism

Fig. 14.1 6-MP metabolism in bone marrow cells. 6-TIMP, 6-thioinosine monophosphate 6-mMP, 6-methylmercapto-purine 6-mTIMP, 6-methyl-thioinosine monophosphate.

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. 

The risk of bone marrow depression by cytostatic drugs is potentiated by allopurinol, which also appears to potentiate the therapeutic effect of purine cytostatic drugs, since it competitively inhibits their metabolic breakdown. Studies in animals suggest that this reaction occurs only with oral mercaptopurine (28), although there is older evidence that the toxicity of cyclophosphamide and other cytostatic drugs can be increased by allopurinol (SED-9, 156). The danger of combining allopurinol with azathioprine has been confirmed by cases of bone marrow suppression, particularly in patients with impaired renal function (SEDA-16,114). 

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. 

With aminopterin, the reductase forms a complex with a low dissociation constant. Thus, in the presence of aminopterin many of the reductase molecules are trapped in an inactive form. The coenzymes necessary for purine biosynthesis are not formed, and that pathway is blocked. In this manner aminopterin interferes with the progress of leukemia and with the proliferation of normal bone marrow. Unfortunately, the cells of individuals treated for leukemia overcome the metabolic block by building up a resistance to the antimetabolites by increasing the level of the reductase. We will now consider the mechanism of action of each of these coenzymes separately. 

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. 

Lu KH, Winnick T. Studies of nucleic acid metabolism in embryonic tissue culture with the aid of C -labeled purines. Exp Cell Res 6 345-352, 1954. See also Lajtha CP, Oliver R, Ellis, F. Incorporation of P and adenine- C into DNA by human bone marrow cells in... 

The broad spectrum of clinical presentation highlights the importance of particular steps in purine and pyrimidine metabolism to different cells and tissues and should have assisted in the development of appropriate treatment. Unfortunately, only three of the nineteen disorders described can be treated successfully hereditary orotic aciduria with life-long uridine, 2,8-di-hydroxyadenine lithiasis with allopurinol. ADA deficiency is treatable by bone marrow transplantation (BHT), or enzyme replacement with polyethylene glycol (PEG)-ADA, but the cost is prohibitive. Er/throcyte-encapsu-lated ADA is effective and less expensive. Oral ribose is reportedly beneficial in myoadenylate deaminase deficiency [1, 4] and also in adenylosucci-nase deficiency [1, 5]. PNP deficiency is also treatable by BMI. 

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