Carbon monoxide: a critical quantitative analysis and review of the extent and limitations of its second messenger function

David G Levitt,1 Michael D Levitt2 1Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, USA; 2Research Service, Veterans Affairs Medical Center, Minneapolis, MN, USA Abstract: Endogenously produced carbon monoxide (CO) is commonly believed to be a ubiquitous...

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Autores principales:	Levitt DG, Levitt MD
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2015
Materias:	Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/37d7564ed99d4df99a04be7c207377c4
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spelling	oai:doaj.org-article:37d7564ed99d4df99a04be7c207377c42021-12-02T02:54:34ZCarbon monoxide: a critical quantitative analysis and review of the extent and limitations of its second messenger function1179-1438https://doaj.org/article/37d7564ed99d4df99a04be7c207377c42015-02-01T00:00:00Zhttp://www.dovepress.com/carbon-monoxide-a-critical-quantitative-analysis-and-review-of-the-ext-peer-reviewed-article-CPAAhttps://doaj.org/toc/1179-1438 David G Levitt,1 Michael D Levitt2 1Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, USA; 2Research Service, Veterans Affairs Medical Center, Minneapolis, MN, USA Abstract: Endogenously produced carbon monoxide (CO) is commonly believed to be a ubiquitous second messenger involved in a wide range of physiological and pathological responses. The major evidence supporting this concept is that CO is produced endogenously via heme oxygenase-catalyzed breakdown of heme and that experimental exposure to CO alters tissue function. However, it remains to be conclusively demonstrated that there are specific receptors for CO and that endogenous CO production is sufficient to alter tissue function. Unlike other signaling molecules, CO is not significantly metabolized, and it is removed from cells solely via rapid diffusion into blood, which serves as a near infinite sink. This non-metabolizable nature of CO renders the physiology of this gas uniquely susceptible to quantitative modeling. This review analyzes each of the steps involved in CO signaling: 1) the background CO partial pressure (PCO) and the blood and tissue CO binding; 2) the affinity of the putative CO receptors; 3) the rate of endogenous tissue CO production; and 4) the tissue PCO that results from the balance between this endogenous CO production and diffusion to the blood sink. Because existing data demonstrate that virtually all endogenous CO production results from the routine “housekeeping” turnover of heme, only a small fraction can play a signaling role. The novel aspect of the present report is to demonstrate via physiological modeling that this small fraction of CO production is seemingly insufficient to raise intracellular PCO to the levels required for the conventional, specific messenger receptor activation. It is concluded that the many physiological alterations observed with exogenous CO administration are probably produced by the non-specific CO inhibition of cytochrome C oxidase activity, with release of reactive oxygen species (ROS) and that this ROS signaling pathway is a potential effector mechanism for endogenously produced CO. Keywords: cytochrome, oxygenase, Krogh cylinder model, ROS, hemeLevitt DGLevitt MDDove Medical PressarticleTherapeutics. PharmacologyRM1-950ENClinical Pharmacology: Advances and Applications, Vol 2015, Iss default, Pp 37-56 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Therapeutics. Pharmacology RM1-950
spellingShingle	Therapeutics. Pharmacology RM1-950 Levitt DG Levitt MD Carbon monoxide: a critical quantitative analysis and review of the extent and limitations of its second messenger function
description	David G Levitt,1 Michael D Levitt2 1Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, USA; 2Research Service, Veterans Affairs Medical Center, Minneapolis, MN, USA Abstract: Endogenously produced carbon monoxide (CO) is commonly believed to be a ubiquitous second messenger involved in a wide range of physiological and pathological responses. The major evidence supporting this concept is that CO is produced endogenously via heme oxygenase-catalyzed breakdown of heme and that experimental exposure to CO alters tissue function. However, it remains to be conclusively demonstrated that there are specific receptors for CO and that endogenous CO production is sufficient to alter tissue function. Unlike other signaling molecules, CO is not significantly metabolized, and it is removed from cells solely via rapid diffusion into blood, which serves as a near infinite sink. This non-metabolizable nature of CO renders the physiology of this gas uniquely susceptible to quantitative modeling. This review analyzes each of the steps involved in CO signaling: 1) the background CO partial pressure (PCO) and the blood and tissue CO binding; 2) the affinity of the putative CO receptors; 3) the rate of endogenous tissue CO production; and 4) the tissue PCO that results from the balance between this endogenous CO production and diffusion to the blood sink. Because existing data demonstrate that virtually all endogenous CO production results from the routine “housekeeping” turnover of heme, only a small fraction can play a signaling role. The novel aspect of the present report is to demonstrate via physiological modeling that this small fraction of CO production is seemingly insufficient to raise intracellular PCO to the levels required for the conventional, specific messenger receptor activation. It is concluded that the many physiological alterations observed with exogenous CO administration are probably produced by the non-specific CO inhibition of cytochrome C oxidase activity, with release of reactive oxygen species (ROS) and that this ROS signaling pathway is a potential effector mechanism for endogenously produced CO. Keywords: cytochrome, oxygenase, Krogh cylinder model, ROS, heme
format	article
author	Levitt DG Levitt MD
author_facet	Levitt DG Levitt MD
author_sort	Levitt DG
title	Carbon monoxide: a critical quantitative analysis and review of the extent and limitations of its second messenger function
title_short	Carbon monoxide: a critical quantitative analysis and review of the extent and limitations of its second messenger function
title_full	Carbon monoxide: a critical quantitative analysis and review of the extent and limitations of its second messenger function
title_fullStr	Carbon monoxide: a critical quantitative analysis and review of the extent and limitations of its second messenger function
title_full_unstemmed	Carbon monoxide: a critical quantitative analysis and review of the extent and limitations of its second messenger function
title_sort	carbon monoxide: a critical quantitative analysis and review of the extent and limitations of its second messenger function
publisher	Dove Medical Press
publishDate	2015
url	https://doaj.org/article/37d7564ed99d4df99a04be7c207377c4
work_keys_str_mv	AT levittdg carbonmonoxideacriticalquantitativeanalysisandreviewoftheextentandlimitationsofitssecondmessengerfunction AT levittmd carbonmonoxideacriticalquantitativeanalysisandreviewoftheextentandlimitationsofitssecondmessengerfunction
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Carbon monoxide: a critical quantitative analysis and review of the extent and limitations of its second messenger function

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