Rat liver-mediated metabolism of hydroxyurea to nitric oxide

Free Radical Biology & Medicine
Jinming HuangS Bruce King

Abstract

Hydroxyurea is an approved treatment for sickle cell disease. Oxidation of hydroxyurea results in the formation of nitric oxide (NO), which also has drawn considerable interest as a sickle cell disease therapy. Although patients on hydroxyurea demonstrate elevated levels of nitric oxide-derived metabolites, little information regarding the site or mechanism of the in vivo conversion of hydroxyurea to nitric oxide exists. Chemiluminescence detection experiments show the ability of crude rat liver homogenate to convert hydroxyurea to nitrite/nitrate, evidence for NO production. Nitrite/nitrate form at therapeutic concentrations of hydroxyurea in a clinically relevant time frame. Electron paramagnetic resonance (EPR) studies show the formation of iron nitrosyl complexes during this incubation and experiments with labeled hydroxyurea show the NO derives from the drug. Gas chromatography-mass spectrometry measurements indicate the hydrolysis of hydroxyurea to hydroxylamine in this system. Incubation of hydroxylamine with crude rat liver homogenate also generates nitrite/nitrate and iron nitrosyl complexes. A line of evidence including inhibitor studies, EPR spectroscopy, and nitrite/nitrate detection identifies catalase as a possibl...Continue Reading

References

Sep 1, 1968·Journal of Pharmaceutical Sciences·J DreyfussS M Hess
Jan 10, 1995·Archives of Biochemistry and Biophysics·W ChamulitratL Molina y Vedia
Jan 13, 1998·Molecular Pharmacology·J JiangR P Mason
May 13, 1999·Biochimica Et Biophysica Acta·C E Cooper
Dec 26, 2001·Proceedings of the National Academy of Sciences of the United States of America·M AslanB A Freeman
Feb 14, 2002·British Journal of Haematology·Mark T GladwinGriffin P Rodgers
Mar 28, 2002·Journal of the American Chemical Society·Jinming HuangS Bruce King
Apr 11, 2002·Chemical Reviews·Peng George WangAdam J Janczuk
Nov 12, 2002·Nature Medicine·Christopher D ReiterMark T Gladwin
Nov 20, 2002·British Journal of Haematology·Masoud NahavandiOswaldo Castro
Jan 25, 2003·British Journal of Haematology·Christina Halsey, Irene A Roberts
Feb 7, 2003·Current Medicinal Chemistry·S Bruce King
Feb 13, 2003·Current Opinion in Hematology·Christopher D Reiter, Mark T Gladwin
Apr 4, 2003·JAMA : the Journal of the American Medical Association·Martin H SteinbergMichael Terrin
Jul 26, 2003·Biochimica Et Biophysica Acta·Virginia L LockamyDaniel B Kim-Shapiro
Mar 1, 1958·The Biochemical Journal·E MARGOLIASH, A NOVOGRODSKY
Aug 1, 1964·Archives of Biochemistry and Biophysics·M L BERNHEIM
Jun 25, 2004·Journal of Medicinal Chemistry·Jinming HuangS Bruce King

❮ Previous
Next ❯

Citations

Dec 22, 2010·Neurogenetics·Cheng XuChing H Wang
May 23, 2013·Toxicological Sciences : an Official Journal of the Society of Toxicology·Ava E Schlisser, Barbara F Hales
Sep 24, 2011·Journal of Pediatric Hematology/oncology·Masanori HayashiCourtney Thornburg
Aug 7, 2009·Experimental Biology and Medicine·Tzu-Fang LouBetty S Pace
May 15, 2009·International Journal of Environmental Research and Public Health·Kea M JonesAnthony E Archibong
Feb 18, 2014·Nitric Oxide : Biology and Chemistry·Sarah Y LockwoodDana M Spence
Feb 2, 2010·Hematology/oncology Clinics of North America·Matthew M Heeney, Russell E Ware
Apr 3, 2008·Pediatric Clinics of North America·Matthew M Heeney, Russell E Ware
Oct 13, 2009·Fundamental & Clinical Pharmacology·Hind SassiAnne Hulin
Jul 1, 2015·British Journal of Haematology·Kenneth I Ataga, Jonathan Stocker
Oct 25, 2016·Translational Research : the Journal of Laboratory and Clinical Medicine·Michael TarasevSumita Chakraborty
Aug 30, 2013·American Journal of Physiology. Cell Physiology·Aisha L WalkerAlex Sparreboom
Apr 9, 2013·Pharmacological Reports : PR·Joanna SchwenkgrubAndrzej Członkowski
Sep 13, 2018·The Pharmacogenomics Journal·Sètondji Cocou Modeste Alexandre YahouédéhouMarilda de Souza Gonçalves
Jan 1, 2018·Expert Opinion on Orphan Drugs·Kenneth I Ataga, Payal C Desai
Aug 9, 2020·F1000Research·Parul Rai, Kenneth I Ataga
Oct 6, 2020·Frontiers in Pharmacology·Sètondji Cocou Modeste Alexandre YahouédéhouMarilda Souza Goncalves
Nov 27, 2020·Journal of Applied Toxicology : JAT·Madelyn C HuangBarry S McIntyre

❮ Previous
Next ❯

Related Concepts

Related Feeds

Anemia

Anemia develops when your blood lacks enough healthy red blood cells. Anemia of inflammation (AI, also called anemia of chronic disease) is a common, typically normocytic, normochromic anemia that is caused by an underlying inflammatory disease. Here is the latest research on anemia.

Blood And Marrow Transplantation

The use of hematopoietic stem cell transplantation or blood and marrow transplantation (bmt) is on the increase worldwide. BMT is used to replace damaged or destroyed bone marrow with healthy bone marrow stem cells. Here is the latest research on bone and marrow transplantation.