Vascular biotransformation of organic nitrates is independent of cytochrome P450 monooxygenases

  • Background and Purpose: Organic nitrates such as nitroglycerin (NTG) or pentaerythritol tetranitrate (PETN) have been used for over a century in the treatment of angina or ischaemic heart disease. These compounds are prodrugs which release their nitrovasodilators upon enzymic bioactivation by aldehyde dehydrogenase (ALDH2) or cytochromes P450 (CYP). Whereas ALDH2 is known to directly activate organic nitrates in vessels, the contribution of vascular CYPs is unknown and was studied here. Experimental Approach: As all CYPs depend on cytochrome P450 reductase (POR) as electron donor, we generated a smooth muscle cell-specific, inducible knockout mouse of POR (smcPOR−/−) to investigate the contribution of POR/CYP to vascular biotransformation of organic nitrates. Key Results: Microsomes containing recombinant CYPs expressed in human vascular tissues released nitrite from NTG and PETN with CYP2C9 and CYP2C8 being most efficient. SFK525, a CYP suicide inhibitor, blocked this effect. smcPOR−/− mice exhibited no obvious cardiovascular phenotype (normal cardiac weight and endothelium-dependent relaxation) and plasma and vascular nitrite production was similar to control (CTL) animals. NTG- and PETN-induced relaxation of isolated endothelium-intact or endothelium-denuded vessels were identical between CTL and smcPOR−/−. Likewise, nitrite release from organic nitrates in aortic rings was not affected by deletion of POR in smooth muscle cells (SMCs). In contrast, inhibition of ALDH2 by benomyl (10 μM) inhibited NTG-induced nitrite production and relaxation. Deletion of POR did not modulate this response. Conclusions and Implications: Our data suggest that metabolism by vascular CYPs does not contribute to the pharmacological function of organic nitrates.

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Author:Melina López SciarraORCiDGND, Pedro Felipe MalacarneORCiDGND, Anna Gajos-DrausORCiD, Xinxin Ding, Andreas DaiberORCiDGND, Jon O. Lundberg, Stefan OffermannsORCiDGND, Ralf BrandesORCiDGND, Flávia Figueiredo de Rezende FelipeORCiDGND
Parent Title (English):British journal of pharmacology
Place of publication:Malden, MA
Document Type:Article
Date of Publication (online):2021/01/15
Date of first Publication:2021/01/15
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2021/11/03
Tag:ALDH2; POR; cytochrome P450 enzymes; cytochrome P450 reductase; nitroglycerin; organic nitrates; pentaerythritol tetranitrate
Page Number:12
First Page:1495
Last Page:1506
This study was supported by the Deutsche Forschungsgemeinschaft “Vaskuläre Funktion der Cytochrom P450-Reduktase (POR)” to F.R., the Faculty of Medicine, Goethe-Universität, Frankfurt am Main, Germany (Forschungsförderung to F.R.), and the Heinrich und Fritz-Riese Stiftung to F.R. Open access funding enabled and organized by Projekt DEAL.

R.P.B. provided conceptual ideas and funding and wrote the manuscript; F.R. provided conceptual ideas and funding and wrote the manuscript. All authors read, revised, and approved the manuscript
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (English):License LogoCreative Commons - Namensnennung-Nicht kommerziell 4.0