Characterization of the mechanism of cytochrome P450 reductase-cytochrome P450-mediated nitric oxide and nitrosothiol generation from organic nitrates

The Journal of Biological Chemistry
Haitao LiJay Zweier

Abstract

Mammalian cytochrome P450 reductase (CPR) and cytochrome P450 (CP) play important roles in organic nitrate bioactivation; however, the mechanism by which they convert organic nitrate to NO remains unknown. Questions remain regarding the initial precursor of NO that serves to link organic nitrate to the activation of soluble guanylyl cyclase (sGC). To characterize the mechanism of CPR-CP-mediated organic nitrate bioactivation, EPR, chemiluminescence NO analyzer, NO electrode, and immunoassay studies were performed. With rat hepatic microsomes or purified CPR, the presence of NADPH triggered organic nitrate reduction to NO2(-). The CPR flavin site inhibitor diphenyleneiodonium inhibited this NO2(-) generation, whereas the CP inhibitor clotrimazole did not. However, clotrimazole greatly inhibited NO2(-)-dependent NO generation. Therefore, CPR catalyzes organic nitrate reduction, producing nitrite, whereas CP can mediate further nitrite reduction to NO. Nitrite-dependent NO generation contributed <10% of the CPR-CP-mediated NO generation from organic nitrates; thus, NO2(-) is not the main precursor of NO. CPR-CP-mediated NO generation was largely thiol-dependent. Studies suggested that organic nitrite (R-O-NO) was produced from org...Continue Reading

References

Aug 1, 1977·Proceedings of the National Academy of Sciences of the United States of America·W P ArnoldF Murad
Dec 1, 1990·Canadian Journal of Physiology and Pharmacology·B J McDonald, B M Bennett
Sep 29, 1989·Biochemical and Biophysical Research Communications·D ServentM Lenfant
May 1, 1988·Journal of Molecular and Cellular Cardiology·C Romanin, W R Kukovetz
Jun 1, 1971·The Biochemical Journal·I H Burger, C L Walters
Mar 1, 1984·Acta Pharmacologica Et Toxicologica·L A ShinobuM M Jones
Aug 1, 1995·Nature Medicine·J L ZweierP Kuppusamy
Aug 11, 1995·The Journal of Biological Chemistry·Y Xia, J L Zweier
Jul 1, 1994·Trends in Pharmacological Sciences·B M BennettW C Simon
Jan 7, 1993·Biochemical Pharmacology·B J McDonald, B M Bennett
Aug 29, 1998·Archives of Biochemistry and Biophysics·A SamouilovJ L Zweier
Mar 14, 2000·The Journal of Biological Chemistry·B L GodberR Harrison
Jul 25, 2000·Biochemical and Biophysical Research Communications·N Grosser, H Schröder
Jan 3, 2001·Proceedings of the National Academy of Sciences of the United States of America·O DöhrC R Wolf
Jun 23, 2001·Biochimica Et Biophysica Acta·J J DoelR Harrison
Jul 5, 2001·Proceedings of the National Academy of Sciences of the United States of America·Y MeahV Massey
Jun 6, 2002·Proceedings of the National Academy of Sciences of the United States of America·Zhiqiang ChenJonathan S Stamler
Feb 10, 2004·The Journal of Biological Chemistry·Haitao LiJay L Zweier

❮ Previous
Next ❯

Citations

Jun 1, 2011·European Journal of Nutrition·Ajay Machha, Alan N Schechter
Oct 7, 2008·The Journal of Biological Chemistry·Martin FeelischHouman Ashrafian
Mar 12, 2008·Antioxidants & Redox Signaling·Kejing ChenAleksander S Popel
Feb 7, 2012·Antioxidants & Redox Signaling·Nicoletta CastiglioneFrancesca Cutruzzolà
Jan 15, 2013·Antioxidants & Redox Signaling·Michele UmbrelloMervyn Singer
Jun 10, 2008·American Journal of Physiology. Heart and Circulatory Physiology·Wael F AlzawahraJay L Zweier
Feb 3, 2009·Biological & Pharmaceutical Bulletin·Shvetambri AroraVirinder Singh Parmar
Jan 15, 2014·Current Opinion in Nephrology and Hypertension·Emmanuel Buys, Patrick Sips
Dec 1, 2008·Expert Opinion on Drug Discovery·Vincenzo Calderone
Mar 28, 2013·Toxicology and Applied Pharmacology·Palanivel GajalakshmiSuvro Chatterjee
Feb 1, 2011·Nitric Oxide : Biology and Chemistry·Daniel MurilloSruti Shiva
Jan 2, 2010·Nitric Oxide : Biology and Chemistry·Jay L ZweierXiaoping Liu
Oct 27, 2015·Journal of Pharmacological Sciences·Yingzi ZhaoSusan W S Leung
Feb 17, 2009·Medicinal Research Reviews·Ernst E van FaassenMark T Gladwin
Sep 26, 2013·Nitric Oxide : Biology and Chemistry·Amedea B SeabraAnn M English
Jan 16, 2015·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Luisa B Maia, José J G Moura
Apr 27, 2016·Free Radical Biology & Medicine·Donald J HirshKay D Bidle
Jan 20, 2017·The Proceedings of the Nutrition Society·Julie A LovegroveDitte A Hobbs
Apr 4, 2014·Chemical Reviews·Luisa B Maia, José J G Moura
Jan 22, 2019·Scientific Reports·Karine F Ferri-LagneauTinChung Leung
Sep 26, 2012·The Journal of Pharmacology and Experimental Therapeutics·Yingzi ZhaoSusan W S Leung
Mar 26, 2010·Critical Care Medicine·Cameron Dezfulian, Stephen Trzeciak
Nov 1, 2018·Physiological Reviews·Jesús TejeroMark T Gladwin
Nov 11, 2020·European Journal of Medicinal Chemistry·Sara ConsalviMariangela Biava
Jul 28, 2021·Inorganic Chemistry·Matthew R DentMark T Gladwin
Sep 28, 2021·Vascular Medicine·Saranya RajendranSuvro Chatterjee

❮ Previous
Next ❯

Related Concepts

Related Feeds

ASBMB Publications

The American Society for Biochemistry and Molecular Biology (ASBMB) includes the Journal of Biological Chemistry, Molecular & Cellular Proteomics, and the Journal of Lipid Research. Discover the latest research from ASBMB here.

Antianginal Drugs: Mechanisms of Action

Antianginal drugs, including nitrates, beta-blockers, and calcium channel blockers, are used in the treatment of angina pectoris. Here is the latest research on their use and their mechanism of action.