Mechanism of allopurinol-mediated increase in enzyme activity in man

Thomas D. Beardmore; Jay S. Cashman; William N. Kelley

doi:10.1172/JCI106984

¹Division of Rheumatic and Genetic Diseases, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710

Find articles by Beardmore, T. in: PubMed | Google Scholar

¹Division of Rheumatic and Genetic Diseases, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710

Find articles by Cashman, J. in: 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: PubMed | Google Scholar

Published in Volume 51, Issue 7 on July 1, 1972
J Clin Invest. 1972;51(7):1823–1832. https://doi.org/10.1172/JCI106984.
© 1972 The American Society for Clinical Investigation

Published July 1, 1972 - Version history

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.