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Research Article Free access | 10.1172/JCI106984
1Division of Rheumatic and Genetic Diseases, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710
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1Division of Rheumatic and Genetic Diseases, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710
Find articles by Cashman, J. in: JCI | PubMed | Google Scholar
1Division of Rheumatic and Genetic Diseases, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710
Find articles by Kelley, W. in: JCI | PubMed | Google Scholar
Published July 1, 1972 - More info
Allopurinol therapy in man interferes with pyrimidine biosynthesis de novo by inhibition of one or both of the two enzymes, orotate phosphoribosyltransferase (OPRT) and orotidylic decarboxylase (ODC), responsible for the conversion of orotic acid to uridine-5′-monophosphate. Inhibition of this pathway in vivo is followed in 1-3 wk by an increase in the activity of both of these enzymes in erythrocytes and of ODC in circulating leukocytes. This drug-mediated increase in enzyme activity in erythrocytes could not be attributed to enzyme stabilization or induction in vivo but appeared to be due to enzyme “activation.” “Activation” of the OPRT enzyme was directly demonstrated in erythrocytes studied in vitro after incubation with oxipurinol, and to a lesser extent, with allopurinol. No evidence for “activation” of the ODC enzyme was demonstrated in vitro. This response to allopurinol therapy provides an excellent model for examining the mechanism of increased enzyme activity in response to drug administration.