ISSN: 2161-0479
Journal of Autacoids and Hormones
Make the best use of Scientific Research and information from our 700+ peer reviewed, 黑料网 Journals that operates with the help of 50,000+ Editorial Board Members and esteemed reviewers and 1000+ Scientific associations in Medical, Clinical, Pharmaceutical, Engineering, Technology and Management Fields.
Meet Inspiring Speakers and Experts at our 3000+ Global Events with over 600+ Conferences, 1200+ Symposiums and 1200+ Workshops on Medical, Pharma, Engineering, Science, Technology and Business
Editorial 黑料网
The Therapeutic Potential of Gaseous Autacoids
| William Durante* | ||
| Department of Medical Pharmacology and Physiology, University of Missouri-Columbia School of Medicine, Columbia, MO, USA | ||
| Corresponding Author : | William Durante, Ph.D Department of Medical Pharmacology and Physiology University of Missouri-Columbia School of Medicine M409 Medical Sciences Building One Hospital Drive, Columbia MO 65212, USA Tel: 573-882-3886 Fax: 573-884-4276 E-mail: durantew@health.missouri.edu |
|
| Received May 04, 2012; Accepted May 04, 2012; Published May 07, 2012 | ||
| Citation: Durante W (2012) The Therapeutic Potential of Gaseous Autacoids. J Autacoids 1:e108. doi: 10.4172/2161-0479.1000e108 | ||
| Copyright: © 2012 Durante W. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. | ||
Related article at Pubmed |
||
Visit for more related articles at Journal of Autacoids and Hormones
| Editorial | |
| Carbon Monoxide (CO) and Hydrogen Sulfide (H2S) are small, lipid-soluble gaseous autacoids that modulate numerous physiological processes. Historically, both gases were considered highly noxious environmental hazard shaving well-defined modes of toxicity: CO binds avidly to hemoglobin reducing the oxygen-carrying capacity of the protein leading to tissue hypoxia while H2S is a potent mitochondrial poison that blocks cellular respiration. Surprisingly, research conducted in the past couple of decades discovered that CO and H2S are produced endogenously by mammalian cells and serve as important signaling molecules in the nervous, inflammatory, and cardiovascular systems. Recent experimental studies indicate that these gases act as vasodilators and elicit broad-spectrum anti-inflammatory, antioxidant, growthregulatory, and cytoprotective effects in animal models of hypertension, inflammation, sepsis, atherosclerosis, transplantation, and ischemiareperfusion injury [1-4]. These preclinical findings underscore the wide-ranging therapeutic potential of CO and H2S, and offer novel translational opportunities in treating multiple human diseases. | |
| CO is a colorless, tasteless, odorless gas that is produced primarily from the degradation of heme by a family of enzymes known as Heme Oxygenase (HO). Molecular cloning identified three isoforms of HO. HO-1 is a ubiquitously distributed and highly inducible isoform that functions in an adaptive manner to limit tissue injury, largely through the release of bile pigments and CO. HO-2 is a constitutively expressed isozyme that is activated by calcium/calmodulin and plays an important role in neurotransmission. A third isoform, HO-3, is nearly devoid of activity and likely represents a pseudogene derived from the HO-2 transcript. In contrast to CO, H2S is a colorless but flammable gas with the characteristic odor of rotten eggs. H2S is generated from cysteine by the action of three enzymes: Cystathionine-β-Synthase (CBS), Cystathione-γ-lyase (CSE), and 3-mercaptopyruvate sulfur transferase (3-MPST). These enzymes exhibit selective tissue distribution with CBS and 3-MPST responsible for a majority of H2S synthesis in the central nervous system while CSE, a calcium/calmodulin-sensitive enzyme, is the predominant source in the cardiovascular system. However, H2S is also formed non-enzymatically from various sulfur-containing compounds. Interestingly, reciprocal regulatory interactions between gaseous autacoids have been identified that may influence their biological activities. In particular, H2S may stimulate the synthesis of CO by inducing the expression of HO-1 while physiologically relevant concentrations of CO inhibits H2S production by blocking the activity of CBS [5,6]. Significant cross-talk between these gases and Nitric Oxide (NO) is also observed. NO stimulates HO-1 gene transcription and CO synthesis whereas CO represses NO formation by attenuating nitric oxide synthase activity [7,8]. Complex functional interactions between NO and H2S have also been reported with H2S either amplifying or attenuating the biological actions of H2S [9]. In addition, NO increases CSE activity and expression while low concentrations of H2S have been shown to enhance the release of NO. | |
| CO and H2S elicit many similar physiological actions that may underlie the salutary profile of these gases in various pathological states. Both CO and H2S are able to preserve blood flow and blood pressure by dilating blood vessels. They also regulate cell growth and death by influencing the expression or activity of proteins that comprise the cell cycle and apoptotic machinery, respectively. In addition, CO and H2S repress mitochondrial respiration by blocking cytochrome c oxidase activity. Both gases also evoke antioxidant effects by inducing the expression of antioxidant genes and, in the case of H2S, by directly reacting with free radicals. Moreover, both CO and H2S possess potent anti-inflammatory properties. However, the molecular mechanism by which these autacoids achieve these effects can differ between the two gases. CO is a relatively stable gas that reacts exclusively with reduced transition metals in metallo enzymes. The interaction of CO with metal centers in heme proteins causes conformational changes in protein structure, which impacts their enzymatic activity in a positive or negative manner. For example, the binding of CO to the heme moiety of soluble guanylatecyclase activates the enzyme leading to a rise in intracellular cGMP levels and vasodilation [10]. In contrast, the binding of CO to cytochrome c oxidase inhibits enzymatic activity and this underlies the anti-inflammatory actions of the gas [11]. Like CO, H2S also binds to specific metal groups in enzymes. However, unlike CO, H2S is chemically reactive and directly interacts with free radicals to form hydrogen sulfide. In addition, sulfide reacts with disulfide or sulfhydryl groups to generate persulfides. Importantly, H2S can modify protein function via the electrophoretic addition of H2S to specific target cysteine residues. In this respect, the ability of H2S to dilate blood vessels does not involve the activation of soluble guanylatecyclase but rather the opening of ATP-sensitive potassium channels following the sulfhydration of a single cysteine residue [12]. In addition, the sulfhydration of nuclear factor kappa-light chain enhancer of activated B cells (NF-κB) by H2S contribute its anti-apoptotic actions [13]. The sulfhydration of proteins by H2S represents a new and potentially widespread signaling mechanism by which this molecule regulates cell function. | |
| Several strategies aimed at exploiting the therapeutic potential of CO and H2S are currently under investigation. Inhalation of CO has proven highly effective in animal models and initial clinical studies indicate that acute, episodic inhalation of low concentrations of CO is well tolerated, safe, and of potential benefit to patients with chronic obstructive pulmonary disease [14]. However, further studies are needed to confirm the safety and efficacy of CO inhalation in treating human lung disease. While administration of CO by inhalation is wellsuited for the treatment of respiratory disorders, inhalation of CO at doses required to achieve therapeutically effective concentrations of the gas in peripheral tissues may be limited by the high affinity of hemoglobin for CO in the circulation and the development of systemic hypoxia. The use of pro-drugs, such as methylene chloride, provides an alternative vehicle for the systemic administration of CO. Oral ingestion of methylene chloride results in the release of CO secondary to its metabolism by cytochrome P450 isozymes. However, there are serious concerns with toxicity related to the use of this compound. A more promising approach in delivering CO involves the use of COReleasing Molecules (CORMs) that liberate CO under physiologic conditions. Numerous CORMs have been synthesized with various solubility and release kinetics and their biological activity corroborated in diverse experimental settings [2]. These compounds allow for a more controlled release of CO and may elevate local levels of CO without significantly increasing carboxy hemoglobin levels. In addition, the design of tissue-selective CORMs may permit disease-specific targeting of CO. | |
| The development of sulfide-based therapeutics is in its infancy but it also relies on the use of H2S gas, H2S-releasing compounds, and pro-drugs. Inhalation of H2S has been used successfully in animal studies but waits testing in the clinic [15]. However, concerns related to the toxicity and reactivity of H2S gas tempers enthusiasm for such an approach. Instead, the development of liquid stable forms of sulfides along with H2S-donor drugs is under active exploration. The attachment of a sulfide-releasing moiety to existing drugs in order to increase the potency and/or reduce the side-effects of the parent compound has proven efficacious in preclinical animal models of inflammation and is under evaluation for a large number of off-patent drugs [16]. The employment of pro-drugs that induce the production of sulfide by endogenous metabolic pathways provides another feasible strategy in administering H2S. In fact, the biologically active component of garlic, S-allycysteine, elicits cardiovascular protective effects via its ability to generate sulfide, suggesting a possible dietary approach in delivering H2S [17]. | |
| In conclusion, emerging data on the biological effects of CO and H2S strongly support the development of gaseous autacoidbased therapeutics. The use of inhaled gas, donor molecules, and pro-drugs provide viable options for delivering CO or H2S. Future pharmacokinetic, pharmacodynamic, and toxicological studies are needed to establish safe and optimal delivery platforms for these gases. While the advancement of pharmaceutical applications based on CO and H2S will provide novel therapeutic opportunities in treating disease, the unique chemical properties of these gases present challenges in harnessing their therapeutic potential. | |
| Acknowledgements | |
| The author acknowledges the support of a grant from the National Institutes of Health HL59976. | |
References
- Durante W (2011)
- Motterlini R, Otterbein LE (2010)
- Szabó C (2007)
- Wang R (2012)
- Zuidema MY, Peyton KJ, Fay WP, Durante W, Korthuis RJ (2011)
- Kabil O, Weeks CL, Carballal S, Gherasim C, Alvarez B, et al. (2011)
- Durante W, Kroll MH, Christodoulides N, Peyton KJ, Schafer AI (1997)
- Klatt P, Schmidt K, Mayer B (1992)
- Li L, Hsu A, Moore PK (2009)
- Furchgott RF, Jothianandan D (1991)
- Zuckerbraun BS, Chin BY, Bilban M, d’Avila JC, Rao J, et al. (2007)
- Mustafa AK, Sikka G, Gazi SK, Steppan J, Jung SM, et al. (2011)
- Sen N, Paul BD, Gadalla MM, Mustafa AK, Sen T, et al. (2012)
- Bathoorn E, Slebos DJ, Postma DS, Koeter DS, van Oosterhout AJ, et al. (2007)
- Morrison ML, Blackwood JE, Lockett SL, Iwata A, Winn RK, et al. (2008)
- Wallace JL, Caliendo G, Santagada V, Cirino G (2010)
- Chuah SC, Moore PK, Zhu YZ (2007)
Share This Article
Relevant Topics
Recommended Journals
Article Tools
Article Usage
- Total views: 13387
- [From(publication date):
May-2012 - Nov 22, 2024] - Breakdown by view type
- HTML page views : 8981
- PDF downloads : 4406
