- Email: [email protected]
Antioxidants: unlocking their potential
Environmental Toxicology and Pharmacology 10 (2001) 139– 140 www.elsevier.com/locate/etap
Editorial
Antioxidants: unlocking their potential
In the media, in general as well as the scientific literature, the subject of antioxidants continues to stimulate keen interest. This is probably because of the growing realization that antioxidants are not just involved with major disease processes, such as diabetes and cancer, but conditions such as aging and resistance to disease. Many national publications continue to make bold claims that foodstuffs, supplements and cosmetic products, which contain antioxidants, can greatly improve many aspects of life and health. While there is no doubt that the correct balance between endogenous and exogenous antioxidant capacity is essential to life, many assertions about antioxidant usage made in the popular press are clearly without basis in scientific fact. In addition, the issue of antioxidant consumption seems clouded both by vested commercial interests and some inconsistency in scientific and medical findings, as well as public recommendations. Over the last 25 years, a vast amount of scientific effort has revealed the basis of how living systems exploit potentially damaging but beneficial high-energy chemical reactions within the cell. The roles of reactive species, particularly those of oxygen, in various disease states are now better understood. Indeed, the processes whereby exogenous and endogenous antioxidants protect cell structure and function from reactive species are also well documented. However, use of antioxidants to date in the treatment of human disease states has not been as successful as might have been envisaged, given the promise shown by many agents in vitro. Perhaps the Media’s flawed understanding of these compounds is a reflection of the incomplete scientific picture of in vivo antioxidant function and its place in the treatment of disease states. The aim of this special issue is to provide a snapshot of some current scientific and clinical perceptions of antioxidant function and application. The subject of antioxidants in general can perhaps be conveniently summarized in four overlapping areas. Firstly, our en* Tel.: +44-121-3593611; fax: + 44-121-3590733.
dogenous protective antioxidant systems; secondly, the relationships between our endogenous systems and essential dietary antioxidants; thirdly, clinical applications of antioxidants and fourthly, antioxidant-reactive species relationships in cellular function and the experimental study of disease states. The first contribution to this special edition, from Nicole Cnubben and her colleagues reviews the sheer diversity of the different roles of glutathione, our most important endogenous antioxidant. Although glutathione is often discussed as the thiol alone, the authors emphasize that the agent is part of a precisely coordinated antioxidant system. This involves a surprising range of enzyme sub-systems, from peroxidases and synthetases to multidrug resistance proteins. The second review is from Gavin Arteel and Helmut Sies and examines the detail of the function of selenium as part of the structure of key enzymes in the glutathione system. In addition to glutathione peroxidases, other selenoproteins such as thioredoxin reductase, selenoprotein P and selenomethionine also play vital antioxidant roles. The authors also discuss the highly promising synthetic organoselenium agent ebselen, which has demonstrated anti-inflammatory as well as antioxidant capability. The next group of reviews looks at the functions of three major antioxidants and their interactions with endogenous systems. Giuseppe Paolisso and colleagues examine the potential benefits of vitamin E in endothelial dysfunction and atherosclerotic disease. The in vitro promise of Vitamin E has not entirely translated to the clinic. However, the authors feel that Vitamin E administration will protect diabetic patients from complications, although they harbor some reservations on the safety of such long-term supplementation. My colleagues and I reviewed the current literature on a-lipoic acid. This is a universal antioxidant of great potential and has shown some effectiveness in treating diabetic polyneuropathy. However, as with other antioxidants, it has been difficult in human studies to provide incontravertable evidence of benefit to match early in vitro
1382-6689/01/$ - see front matter © 2001 Elsevier Science B.V. All rights reserved. PII: S1382-6689(01)00076-X
140
Editorial
promise. However, it seems clear that a-lipoic acid will find a place in the mainstream of the treatment of as well as protection from diabetic complications. Helen Griffiths and Joe Lunec have studied some of the variety of roles of ascorbic acid, perhaps the best known antioxidant. Although essential to life, ascorbate shows pro-oxidant effects in certain conditions. The roles of ascorbate in the protection of DNA from oxidant damage and in the modulation of gene expression are also explored. The sixth and seventh contributions look at aspects of both the scientific and clinical applications of antioxidants in fields that are sometimes not immediately associated with their usage. Nicholas Coleman has evaluated the application of antioxidants during the intensive care of the critically ill, such as those with multiple organ dysfunction syndrome. Free radical activity is often responsible for severe injury during tissue reperfusion. Supplementation of combinations of antioxidants have shown benefit in this context, although in some conditions such as acute respiratory distress syndrome and CNS ischaemia, antioxidants have been much less effective. Clare Taylor has reviewed the role of antioxidants in conception and fertility. Antioxidants have been employed with varying degrees of effectiveness to improve male fertility and to protect human gametes and embryos in vitro. This work is ultimately aimed at increasing assisted conception success rates in response to demand from growing numbers of childless couples. The final three reviews concern the experimental use of oxidant agents in antioxidant research and reactive species control of some aspects of cell function. Chantal Heijnen and her colleagues have used peroxynitrite scavenging ability to study some structure activity relationships for a sub-group of flavonoids, the flavonols. These potent antioxidant compounds are found in a variety of foodstuffs from red wine to vegetables. This detailed chemical and mathematical analysis will be essential for the design and synthesis of safer and higher potency flavonoid agents. My second contribution to this edition is based on some previous studies, where diabetic erythrocytes produce less xenobiotic-mediated methaemoglobin compared with non-diabetics, due to compromised oxidant defence systems. I am proposing that the use of the methaemoglobin process in vitro will determine if in vivo antioxidant supplementation actually does eliminate the defects in diabetic oxidant defence systems and restore parity with those of non-diabetics. Finally, Chandan Sen and Sashwati Roy challenge our usual negative perceptions of reactive oxidative species and underscore the vital roles that
these species play in essential cellular processes such as apoptotic cell death. Caspases, which control apoptosis, are regulated by REDOX reactions through glutathione and thioredoxin. The death of damaged cells can be regulated by thiol status, both endogenously and exogenously with agents such as a-lipoic acid, which may be crucial in the therapeutic control of a number of disease states. Overall, our contributors to this issue have shown that some agents have demonstrated clinical benefit in some conditions, although the disparity between the in vitro potential of other antioxidants and their clinical performance remains and may have arisen due to a combination of factors. Primarily, we still lack complete understanding of both the behavior and control of reactive species. This is underlined in the poor clinical outcomes reported for a range of conditions, from paraquat poisoning and reperfusion injury to cancer, diabetes and multiple organ dysfunction. Another problem, is that often antioxidants are required to alleviate clinical conditions which are the product of many years of attrition or severe and acute trauma. Hence, despite their efficient protective functions, restoration of critical structural damage may be beyond the scope of most of their capabilities. The future of antioxidants may lie in the long-term protection of individuals who are at risk from reactive species as well as the stabilization of those already suffering the consequences of damage. This depends on early diagnosis, the relationship between particular supplement dosages and endogenous antioxidants as well as the use of combinations of several agents, rather than large doses of a single agent. Above all, it is necessary to demonstrate conclusively that antioxidant therapy is protecting at risk individuals from oxidant damage. The Journal wishes to thank all the contributors for making the time and the effort to send their work to this special edition. Their dedication, determination and inspiration provide great optimism that antioxidants will continue to alleviate human suffering and ultimately fulfill their potential. Michael D. Coleman* Mechanisms of Drug Toxicity Group, Department of Pharmaceutical Sciences, Aston Uni6ersity, Aston Triangle, Birmingham B4 7ET, UK E-mail: [email protected]
Editorial
Antioxidants: unlocking their potential
In the media, in general as well as the scientific literature, the subject of antioxidants continues to stimulate keen interest. This is probably because of the growing realization that antioxidants are not just involved with major disease processes, such as diabetes and cancer, but conditions such as aging and resistance to disease. Many national publications continue to make bold claims that foodstuffs, supplements and cosmetic products, which contain antioxidants, can greatly improve many aspects of life and health. While there is no doubt that the correct balance between endogenous and exogenous antioxidant capacity is essential to life, many assertions about antioxidant usage made in the popular press are clearly without basis in scientific fact. In addition, the issue of antioxidant consumption seems clouded both by vested commercial interests and some inconsistency in scientific and medical findings, as well as public recommendations. Over the last 25 years, a vast amount of scientific effort has revealed the basis of how living systems exploit potentially damaging but beneficial high-energy chemical reactions within the cell. The roles of reactive species, particularly those of oxygen, in various disease states are now better understood. Indeed, the processes whereby exogenous and endogenous antioxidants protect cell structure and function from reactive species are also well documented. However, use of antioxidants to date in the treatment of human disease states has not been as successful as might have been envisaged, given the promise shown by many agents in vitro. Perhaps the Media’s flawed understanding of these compounds is a reflection of the incomplete scientific picture of in vivo antioxidant function and its place in the treatment of disease states. The aim of this special issue is to provide a snapshot of some current scientific and clinical perceptions of antioxidant function and application. The subject of antioxidants in general can perhaps be conveniently summarized in four overlapping areas. Firstly, our en* Tel.: +44-121-3593611; fax: + 44-121-3590733.
dogenous protective antioxidant systems; secondly, the relationships between our endogenous systems and essential dietary antioxidants; thirdly, clinical applications of antioxidants and fourthly, antioxidant-reactive species relationships in cellular function and the experimental study of disease states. The first contribution to this special edition, from Nicole Cnubben and her colleagues reviews the sheer diversity of the different roles of glutathione, our most important endogenous antioxidant. Although glutathione is often discussed as the thiol alone, the authors emphasize that the agent is part of a precisely coordinated antioxidant system. This involves a surprising range of enzyme sub-systems, from peroxidases and synthetases to multidrug resistance proteins. The second review is from Gavin Arteel and Helmut Sies and examines the detail of the function of selenium as part of the structure of key enzymes in the glutathione system. In addition to glutathione peroxidases, other selenoproteins such as thioredoxin reductase, selenoprotein P and selenomethionine also play vital antioxidant roles. The authors also discuss the highly promising synthetic organoselenium agent ebselen, which has demonstrated anti-inflammatory as well as antioxidant capability. The next group of reviews looks at the functions of three major antioxidants and their interactions with endogenous systems. Giuseppe Paolisso and colleagues examine the potential benefits of vitamin E in endothelial dysfunction and atherosclerotic disease. The in vitro promise of Vitamin E has not entirely translated to the clinic. However, the authors feel that Vitamin E administration will protect diabetic patients from complications, although they harbor some reservations on the safety of such long-term supplementation. My colleagues and I reviewed the current literature on a-lipoic acid. This is a universal antioxidant of great potential and has shown some effectiveness in treating diabetic polyneuropathy. However, as with other antioxidants, it has been difficult in human studies to provide incontravertable evidence of benefit to match early in vitro
1382-6689/01/$ - see front matter © 2001 Elsevier Science B.V. All rights reserved. PII: S1382-6689(01)00076-X
140
Editorial
promise. However, it seems clear that a-lipoic acid will find a place in the mainstream of the treatment of as well as protection from diabetic complications. Helen Griffiths and Joe Lunec have studied some of the variety of roles of ascorbic acid, perhaps the best known antioxidant. Although essential to life, ascorbate shows pro-oxidant effects in certain conditions. The roles of ascorbate in the protection of DNA from oxidant damage and in the modulation of gene expression are also explored. The sixth and seventh contributions look at aspects of both the scientific and clinical applications of antioxidants in fields that are sometimes not immediately associated with their usage. Nicholas Coleman has evaluated the application of antioxidants during the intensive care of the critically ill, such as those with multiple organ dysfunction syndrome. Free radical activity is often responsible for severe injury during tissue reperfusion. Supplementation of combinations of antioxidants have shown benefit in this context, although in some conditions such as acute respiratory distress syndrome and CNS ischaemia, antioxidants have been much less effective. Clare Taylor has reviewed the role of antioxidants in conception and fertility. Antioxidants have been employed with varying degrees of effectiveness to improve male fertility and to protect human gametes and embryos in vitro. This work is ultimately aimed at increasing assisted conception success rates in response to demand from growing numbers of childless couples. The final three reviews concern the experimental use of oxidant agents in antioxidant research and reactive species control of some aspects of cell function. Chantal Heijnen and her colleagues have used peroxynitrite scavenging ability to study some structure activity relationships for a sub-group of flavonoids, the flavonols. These potent antioxidant compounds are found in a variety of foodstuffs from red wine to vegetables. This detailed chemical and mathematical analysis will be essential for the design and synthesis of safer and higher potency flavonoid agents. My second contribution to this edition is based on some previous studies, where diabetic erythrocytes produce less xenobiotic-mediated methaemoglobin compared with non-diabetics, due to compromised oxidant defence systems. I am proposing that the use of the methaemoglobin process in vitro will determine if in vivo antioxidant supplementation actually does eliminate the defects in diabetic oxidant defence systems and restore parity with those of non-diabetics. Finally, Chandan Sen and Sashwati Roy challenge our usual negative perceptions of reactive oxidative species and underscore the vital roles that
these species play in essential cellular processes such as apoptotic cell death. Caspases, which control apoptosis, are regulated by REDOX reactions through glutathione and thioredoxin. The death of damaged cells can be regulated by thiol status, both endogenously and exogenously with agents such as a-lipoic acid, which may be crucial in the therapeutic control of a number of disease states. Overall, our contributors to this issue have shown that some agents have demonstrated clinical benefit in some conditions, although the disparity between the in vitro potential of other antioxidants and their clinical performance remains and may have arisen due to a combination of factors. Primarily, we still lack complete understanding of both the behavior and control of reactive species. This is underlined in the poor clinical outcomes reported for a range of conditions, from paraquat poisoning and reperfusion injury to cancer, diabetes and multiple organ dysfunction. Another problem, is that often antioxidants are required to alleviate clinical conditions which are the product of many years of attrition or severe and acute trauma. Hence, despite their efficient protective functions, restoration of critical structural damage may be beyond the scope of most of their capabilities. The future of antioxidants may lie in the long-term protection of individuals who are at risk from reactive species as well as the stabilization of those already suffering the consequences of damage. This depends on early diagnosis, the relationship between particular supplement dosages and endogenous antioxidants as well as the use of combinations of several agents, rather than large doses of a single agent. Above all, it is necessary to demonstrate conclusively that antioxidant therapy is protecting at risk individuals from oxidant damage. The Journal wishes to thank all the contributors for making the time and the effort to send their work to this special edition. Their dedication, determination and inspiration provide great optimism that antioxidants will continue to alleviate human suffering and ultimately fulfill their potential. Michael D. Coleman* Mechanisms of Drug Toxicity Group, Department of Pharmaceutical Sciences, Aston Uni6ersity, Aston Triangle, Birmingham B4 7ET, UK E-mail: [email protected]