Xanthine oxidase analogue metabolism

The pyrazolo[3, 4-d] pyrimidines are substrates for and inhibitors of xanthine oxidase [266, 267]. 4-Hydroxypyrazolo[3,4-d] pyrimidine was first investigated for its ability to protect 6-mercaptopurine and other analogues from oxidation by xanthine oxidase [384], but it also inhibits the oxidation of the natural purines, hypoxanthine, and xanthine. Its profound effect on uric acid metabolism made it an obvious choice for the treatment of gout and its utility in the control of this disease has been demonstrated [385, 386]. 

The reason for the selective toxicity of 6-mercaptopuiine remains to be established, but two factors may be of primary importance. 6-Mercaptopurine is anabolized primarily, if not exclusively, to the monophosphate level, and it is readily catabolized by xanthine oxidase, an enzyme that is low in most cancer cells compared to normal cells. Another factor that must be considered is the metabolic state of the target cells. Actively proliferating leukaemia cells are more sensitive to 6-mercaptopurine, as they are to all antimetabolites, than cells in the so-called Gq or stationary phase. Although this does not explain the difference between 6-mercaptopurine and other purine analogues, it may explain the ineffectiveness of 6-mercaptopurine against solid tumours, most of the cells of which are in the non-dividing state. 

Certain drugs inhibit non-microsomal metabolic pathways. Metronidazole, like disulfiram, inhibits aldehyde dehydrogenase, the enzyme that normally oxidizes acetaldehyde to acetic acid in the metabolic pathway for ethanol. Allopurinol inhibits xanthine oxidase, the enzyme that catalyses the oxidation of hypoxanthine to xanthine and xanthine to uric acid. Because azathioprine and 6-mercaptopurine are metabolized by xanthine oxidase, the dosage of these drugs (synthetic xanthine analogues), when used concomitantly with... 

The related analogue 6-deoxyacyclovir is a prodrug form of acyclovir that is activated through metabolism by xanthine oxidase. This drug, which has improved solubility characteristics compared to acyclovir, is used for the treatment of VZV infection. 

Pyrazolopyrimidines are purine analogues in which the nitrogen and carbon of the imidazole ring are inverted. The best known member of this group, allopurinol (4-hydroxypyrazolo(3,4-d)pyrimidine HPP), is a structural analogue of hypoxanthine. Its major metabolic conversions in mammalian cells are to oxipurinol, via xanthine oxidase, and to allopurinol ribonucleoside (HPPR)l. 

XANTHINE OXIDASE AND ALDEHYDE OXIDASE IN PURINE AND PURINE ANALOGUE METABOLISM... 

---