Mechanism of allopurinol-mediated increase in enzyme activity in man

The Journal of Clinical Investigation
T D BeardmoreW N Kelley

Abstract

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.

References

Jun 1, 1967·Proceedings of the National Academy of Sciences of the United States of America·W N KelleyJ E Seegmiller
May 2, 1968·The New England Journal of Medicine·R L Baehner, D G Nathan
Apr 1, 1967·Proceedings of the National Academy of Sciences of the United States of America·L Pinsky, R S Krooth
Jun 1, 1970·Proceedings of the National Academy of Sciences of the United States of America·J P Comstock, S Udenfriend
Jul 6, 1971·Annals of the New York Academy of Sciences·R S Krooth
Dec 1, 1969·American Journal of Diseases of Children·D G TubergenR M Heyn
May 15, 1970·Science·R M FoxW J O'Sullivan
Jul 24, 1970·Science·W N Kelley, T D Beardmore
Jul 1, 1968·The American Journal of Medicine·G B ElionG H Hitchings
Aug 1, 1969·The American Journal of Medicine·R M FoxB G Firkin
Feb 1, 1966·Analytical Biochemistry·M Baggiolini, M H Bickel

Citations

Nov 1, 1975·Arthritis and Rheumatism·M A BeckerJ E Seegmiller
Jan 1, 1976·Comparative Biochemistry and Physiology. B, Comparative Biochemistry·W J TaxJ M Trijbels
Mar 18, 1997·Clinica Chimica Acta; International Journal of Clinical Chemistry·J SevcíkV Sázel
Aug 1, 1975·Psychological Medicine·I B CooksonA P Ridges
Apr 12, 1973·The New England Journal of Medicine·L H SMITH
May 1, 1979·British Journal of Haematology·M B van der WeydenB G Firkin
Jan 1, 1980·The Journal of Clinical Investigation·M A BeckerW L Nyhan
Dec 1, 1973·The American Journal of Medicine·R M FoxW J O'Sullivan
Aug 1, 1980·European Journal of Clinical Investigation·H A SimmondsC F Potter

Related Concepts

Caplenal
Carbon Isotopes
Carboxy-Lyases
Depression, Chemical
Drug Tolerance
Enzyme Activation
Erythrocytes
Gout
Leukocytes
Nucleosides

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Synthetic Genetic Array Analysis

Synthetic genetic arrays allow the systematic examination of genetic interactions. Here is the latest research focusing on synthetic genetic arrays and their analyses.

Congenital Hyperinsulinism

Congenital hyperinsulinism is caused by genetic mutations resulting in excess insulin secretion from beta cells of the pancreas. Here is the latest research.

Neural Activity: Imaging

Imaging of neural activity in vivo has developed rapidly recently with the advancement of fluorescence microscopy, including new applications using miniaturized microscopes (miniscopes). This feed follows the progress in this growing field.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Epigenetic Memory

Epigenetic memory refers to the heritable genetic changes that are not explained by the DNA sequence. Find the latest research on epigenetic memory here.

Cell Atlas of the Human Eye

Constructing a cell atlas of the human eye will require transcriptomic and histologic analysis over the lifespan. This understanding will aid in the study of development and disease. Find the latest research pertaining to the Cell Atlas of the Human Eye here.

Femoral Neoplasms

Femoral Neoplasms are bone tumors that arise in the femur. Discover the latest research on femoral neoplasms here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.