SESSION I: SETTING THE SCENE New Frontiers for Antioxidants Douglas E. Brash, Yale School of Medicine Cysteine/Glutathione Deficiency Disease Leonore A. Herzenberg, Stanford University Douglas E. Brash, Ph.D., Professor, Department of Therapeutic Radiology and Genetics, Yale School of Medicine, New Haven, Connecticut, presented an overview of antioxidants and discussed ways in which the study of sulfhydryl switches differs from the classic understanding of oxidant and antioxidant biochemistry, suggesting new frontiers in protein regulation. Leonore A. Herzenberg, Ph.D., Professor, Department of Genetics, Stanford University, California, presented information on pathologies associated with thiol deficiency, and the health benefits associated with thiol-containing medications such as N-acetyl cysteine (NAC). A critical issue in the study of sulfhydryl switches is to understand the interplay between oxidants/antioxidants and the thiol redox system within the cell. For example, can vitamins E and C alter sulfhydryl switches? Addition of many different exogenous compounds (oxidants, antioxidants, reactive metal ions or reactive toxicants such as the quinone imine metabolite of acetaminophen) can readily disrupt normal thiol redox regulation within the cell. This can be either by altering redox or by depleting redox components such as cysteine or glutathione molecules. On the other hand, natural redox modulation within a cell, undistorted by exogenous compounds, may be more subtle, responding to changes that do not reflect the status of the entire cell, and that are rapidly returned to normal: sulfhydryl switches that are switched on, initiate a cascade of events, and are then switched off again. For example, many transcription factors are sensitive to change in redox, such as p53 with its 10 cysteine molecules in the DNA binding domain, open to modification by endogenous mechanisms such as interaction with the thioredoxin reductase- Ref-1 pathway. The importance of thiol status in these signaling molecules is highlighted by the fact that they each require selenium, the biochemistry of which is intimately involved in thiol interactions. Another example of the importance of thiol switches in regulation of intermediary metabolism is the oxidation of protein sulfhydryls which appears to be a common signal for protein degradation. To date, it would appear that all too often the study of the role of sulfhydryl switches in signal transduction has been confounded by gross redox changes triggered by addition of exogenous oxidant tools. Such effects can, of course, be prevented by an excess of antioxidants such as vitamin E either exterior or interior to the cell, but such studies are unlikely to reflect any physiological role of vitamin E. Such massive changes in redox can alter the fine balance of proteins normally regulated by thiol redox such as p53, which in response to small redox changes can switch between DNA repair/ proliferation and apoptosis. Subtle redox changes that more typically regulate cellular pathways, rather than acting directly, may be part of a strictly regulated cascade of metabolic changes. Given then, that thiol regulation is distinct from the action of pro-and anti-oxidants and that its study may be confounded by oxidative damage that can disrupt the thiol balance, disease models rather than chemical intervention models, may be most useful in the study of the biochemistry and physiology of sulfhydryl switches. Cellular metabolism includes an intricate redox regulatory system based on thiol switches that is altered in multiple diseased states and may at times be reversed by feeding a thiol-rich diet or providing medication such as NAC. Oral NAC has been studied in over 50 clinical trials and has, for example, been found effective in improving the immune response in AIDS patients, as well as in a number of other disease states such as cystic fibrosis, for which NAC was first developed. Whether physiological improvement is dependent upon the ability of the drug or diet to alter cellular redox directly, or to provide the essential components such as cysteine, remains to be determined. One possible route for investigating this is to study protein thiolation in different disease states and in the reversal of disease during therapy. The study of thiol physiology and biochemistry has not previously been considered as a whole, possibly because it cuts across multiple fields, including genomics, proteomics, and metabolomics. A listing of major thiol targets would likely be useful in establishing the field. Another concern raised in this session was the need to understand personal differences in thiol status. Epidemiological studies show that dietary antioxidants can decrease cancer risk only to about 0.6 in the general population, whereas individuals at high risk (elderly, smokers, and possibly antioxidant-deficient individuals) can see a drop in risk to about 0.3 of their original risk. Dr. Brash suggested that this may reflect a redundancy in the metabolic pathways in the general population, so that if one pathway fails, another is able to maintain the status quo. If one of the pathways is absent in individuals described as at high risk for a disease, then a disruption of the remaining pathway, even if it is only temporary, can be devastating – whereas continual enhancement of the remaining pathway can relieve the risk caused by the failing alternative pathway. This concept is supported by studies comparing single and multiple knock-out models of cancer. Should some component associated with thiol redox (e.g., glutathione, cysteine, selenium) become limiting, this could jeopardize the proper functioning of a pathway – and if the system has previously lost alternatives due to genotype or environmental factors, this could prove fatal. Alternatively, providing excess of these factors in the diet could overcome the need for the second, non-functional pathway, allowing lowering of risk. Personalized nutrition, based on alleviating faulty pathways, will have an important future in maintaining health in individuals at high risk for certain diseases. August, 2003 NIH meeting Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. Support our work with any size DONATION - see left side of any page - for how to donate. You can help raise awareness of CAM.