Sensitive quantification of carbon monoxide in vivo reveals a protective role of circulating hemoglobin in CO intoxication (original) (raw)
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Use of carbon monoxide as a therapeutic agent: promises and challenges
Roberta FORESTI, MohamedG. BANI-HANIand Roberto MOTTERLINI, 2008
As a by-product of heme catabolism by the heme oxygenase system, carbon monoxide (CO) has been neglected for many years, and only recently has its role as an essential signaling molecule been appreciated. In the past decade, the use of CO gas in pre-clinical experimental models of disease has produced some remarkable data indicating that its therapeutic delivery to mammals could alleviate inflammatory processes and cardiovascular disorders. However, the inherent toxic nature of CO cannot be ignored, knowing that inhalation of uncontrolled amounts of this gas can ultimately lead to serious systemic complications and neuronal derangements. From a clinical perspective, a key question is whether a safe and therapeutically effective threshold of CO can be reached locally in organs and tissues without delivering potentially toxic amounts through the lung. The advent of CO-releasing molecules (CO-RMs), a group of compounds capable of carrying and liberating controlled quantities of CO in cellular systems, appears a plausible alternative in the attempt to overcome the limitations of CO gas. Although in its infancy and far from being used for clinical applications, the CO-RMs technology is supported by very encouraging biological results and reflected by the chemical versatility of these compounds and their endless potential to be transformed into CO-based pharmaceuticals.
J Am Chem Soc ., 2017
Carbon monoxide (CO) is produced in mammalian cells during heme metabolism and serves as an important signaling messenger. Here we report the bioactive properties of selective CO scavengers, hemoCD1 and its derivative R8-hemoCD1, which have the ability to detect and remove endogenous CO in cells. HemoCD1 is a supramolecular hemoprotein-model complex composed of 5,10,15,20-tetrakis(4-sulfonatophenyl)porphinatoiron-(II) and a per-O-methylated β-cyclodextrin dimer having an pyridine linker. We demonstrate that hemoCD1 can be used effectively to quantify endogenous CO in cell lysates by a simple spectrophotometric method. The hemoCD1 assay detected ca. 260 pmol of CO in 10 6 hepatocytes, which was well-correlated with the amount of intracellular bilirubin, the final breakdown product of heme metabolism. We then covalently attached an octaarginine peptide to a maleimide-appended hemoCD1 to synthesize R8-hemoCD1, a cell-permeable CO scavenger. Indeed, R8-hemoCD1 was taken up by intact cells and captured intracellular CO with high efficiency. Moreover, we revealed that removal of endogenous CO by R8-hemoCD1 in cultured macrophages led to a significant increase (ca. 2.5-fold) in reactive oxygen species production and exacerbation of inflammation after challenge with lipopolysaccharide. Thus, R8-hemoCD1 represents a powerful expedient for exploring specific and still unidentified biological functions of CO in cells. 65 f1 1), a supramolecular hemoprotein-model complex that we have 66 studied for the past decade. 23−34 HemoCD1 is composed of
Pitfalls using metalloporphyrins in carbon monoxide research
Trends in Pharmacological Sciences, 1997
The proposal that endogenously produced carbon monoxide (CO) may act as a biological messenger has remained controversial. Carbon monoxide is generated by haem oxygenase isoenzymes in the degradation of haem-containing molecules. Certain metalloporphyrins, which are inhibitors of haem oxygenase, have been widely used as pharmacological tools in order to establish a messenger role for CO in the brain and periphery. However, increasing evidence shows that many metalloporphyrins are also associated with a large range of undesired effects, which make the interpretation of results using such compounds very uncertain. In this article, Lars Grundemar and Lars Ny evaluate the properties and describe the nonselective effect profile of such metalloporphyrins.
Carbon Monoxide-Releasing Molecules: Characterization of Biochemical and Vascular Activities
Roberto MOTTERLINI, James E. CLARK, Roberta FORESTI, Padmini SARATHCHANDRA, Brian E. MANN, Colin J. GREEN, 2002
Carbon monoxide (CO) is generated in living organisms during the degradation of heme by the enzyme heme oxygenase, which exists in constitutive (HO-2 and HO-3) and inducible (HO-1) isoforms. Carbon monoxide gas is known to dilate blood vessels in a manner similar to nitric oxide and has been recently shown to possess antiinflammatory and antiapoptotic properties. We report that a series of transition metal carbonyls, termed here carbon monoxide–releasing molecules (CO-RMs), liberate CO to elicit direct biological activities. Specifically, spectrophotometric and NMR analysis revealed that dimanganese decacarbonyl and tricarbonyldichlororuthenium (II) dimer release CO in a concentration-dependent manner. Moreover, CO-RMs caused sustained vasodilation in precontracted rat aortic rings, attenuated coronary vasoconstriction in hearts ex vivo, and significantly reduced acute hypertension in vivo. These vascular effects were mimicked by induction of HO-1 after treatment of animals with hemin, which increases endogenously generated CO. Thus, we have identified a novel class of compounds that are useful as prototypes for studying the bioactivity of CO. In the long term, transition metal carbonyls could be utilized for the therapeutic delivery of CO to alleviate vascular- and immuno-related dysfunctions. The full text of this article is available at http://www.circresaha.org. (Circ Res. 2002;90:e17-e24.)
Therapeutic Applications of Carbon Monoxide-Releasing Molecules
Roberto Motterlini, Brian E Mann & Roberta Foresti, 2005
Carbon monoxide (CO), which is formed in mammalian cells through the oxidation of haem by the enzyme haem oxygenase, actively participates in the regulation of key intracellular functions. Emerging evidence reveals that an increased generation of haem oxygenase-derived CO plays a critical role in the resolution of inflammatory processes and alleviation of cardiovascular disorders. The authors have identified a novel class of substances, CO-releasing molecules (CO-RMs), which are capable of exerting a variety of pharmacological activities via the liberation of controlled amounts of CO in biological systems. A wide range of CO carriers containing manganese (CORM-1), ruthenium (CORM-2 and -3), boron (CORM-A1) and iron (CORM-F3) are currently being investigated to tailor therapeutic approaches for the prevention of vascular dysfunction, inflammation, tissue ischaemia and organ rejection.
The therapeutic potential of carbon monoxide
Roberto MOTTERLINI and Leo E. OTTERBEIN, 2010
"""Carbon monoxide (CO) is increasingly being accepted as a cytoprotective and homeostatic molecule with important signalling capabilities in physiological and pathophysiological situations. The endogenous production of CO occurs through the activity of constitutive (haem oxygenase 2) and inducible (haem oxygenase 1) haem oxygenases, enzymes that are responsible for the catabolism of haem. Through the generation of its products, which in addition to CO includes the bile pigments biliverdin, bilirubin and ferrous iron, the haem oxygenase 1 system also has an obligatory role in the regulation of the stress response and in cell adaptation to injury. This Review provides an overview of the physiology of CO, summarizes the effects of CO gas and CO-releasing molecules in preclinical animal models of cardiovascular disease, inflammatory disorders and organ transplantation, and discusses the development and therapeutic options for the exploitation of this simple gaseous molecule."""
Biological signaling by carbon monoxide and carbon monoxide-releasing molecules
Am J Physiol Cell Physiol ., 2017
Carbon monoxide (CO) is continuously produced in mammalian cells during the degradation of heme. It is a stable gaseous molecule that reacts selectively with transition metals in a specific redox state, and these characteristics restrict the interaction of CO with defined biological targets that transduce its signaling activity. Because of the high affinity of CO for ferrous heme, these targets can be grouped into heme-containing proteins, representing a large variety of sensors and enzymes with a series of diverse function in the cell and the organism. Despite this notion, progress in identifying which of these targets are selective for CO has been slow and even the significance of elevated carbonmonoxy hemoglobin, a classical marker used to diagnose CO poisoning, is not well understood. This is also due to the lack of technologies capable of assessing in a comprehensive fashion the distribution and local levels of CO between the blood circulation, the tissue, and the mitochondria, one of the cellular compartments where CO exerts its signaling or detrimental effects. Nevertheless, the use of CO gas and CO-releasing molecules as pharmacological approaches in models of disease has provided new important information about the signaling properties of CO. In this review we will analyze the most salient effects of CO in biology and discuss how the binding of CO with key ferrous hemoproteins serves as a posttranslational modification that regulates important processes as diverse as aerobic metabolism, oxidative stress, and mitochondrial bioenergetics.
Cell-free and alkylated hemoproteins improve survival in mouse models of carbon monoxide poisoning
JCI Insight
and granted patents for the use of recombinant neuroglobin and other heme-based molecules as antidotes for carbon monoxide (CO) poisoning (US 2019/0290739 A1, US 2022/0185867 A1, US2019/0389937 A1, WO 2021/231370 A2). JJR and JT are officers and directors of Globin Solutions Inc. MTG is a director, consultant, and advisor of Globin Solutions Inc. Globin Solutions Inc. has licensed this technology. Globin Solutions Inc. had an option to technology directed at using hydroxycobalamin for CO poisoning from Virginia Commonwealth University that expired more than 12 months ago. MTG is a coinventor on patents (US 2010/0247682 A1, US 2018/0360873 A1) directed to the use of nitrite salts in cardiovascular diseases licensed to Globin Solutions Inc. MTG is a coinvestigator in a research collaboration with Bayer Pharmaceuticals to evaluate riociguat as a treatment for patients with sickle cell disease. JJR is a cofounder of Omnibus Medical Devices LLC. and serves as an expert witness to medical legal cases not related to CO poisoning. The financial conflicts of interest of JJR, JT, QX, LW, AWD, CFM, and MTG were managed by the University of Pittsburgh Conflict of Interest Committee and a data stewardship committee.
Analytical Biochemistry, 2005
Carbon monoxide (CO), produced endogenously during heme degradation, is considered a messenger molecule in vascular and neurologic tissues. To study this role, it is important to determine CO concentration in target tissues pre-and post-perturbations. Here, we describe a sensitive and reproducible method, which is linear and accurate, and provide some examples of its application for quantitation of CO concentrations in tissues pre-and post-perturbations. Tissues from adult rats and mice were sonicated (20% w/w), and volumes representing 0.04-8 mg fresh weight (FW) were incubated at 0°C for P30 min with sulfosalicylic acid. CO liberated into the headspace was quantitated by gas chromatography. Tissue CO concentrations (mean ± SD, pmol CO/mg FW) were as follows:
Toward Carbon Monoxide–Based Therapeutics: Critical Drug Delivery and Developability Issues
Journal of Pharmaceutical Sciences, 2016
Carbon monoxide is an intrinsic signaling molecule with importance on par with that of nitric oxide. During the past decade, pharmacological studies have amply demonstrated the therapeutic potential of carbon monoxide. However, such studies were mostly based on CO inhalation and metal-based CO releasing molecules (CO-RMs). The field is now at the stage that a major effort is needed to develop pharmaceutically acceptable forms of CO for delivery via various routes such as oral, injection, infusion, or topical applications. This review examines the state of the art, discusses existing hurdles to overcome, and proposes developmental strategies necessary to address remaining drug delivery issues.