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Hydrogen as a Selective Antioxidant: a Review

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Hydrogen as a Selective Antioxidant: a Review ( hydrogen-as-selective-antioxidant-review )

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2 hydroxyl radical (•OH), hydrogen peroxide (H2O2) and singlet oxygen (1O2). These different species interconvert via cascade reactions. Although generally regarded as toxic by- products, physiological roles have been identified for molecules such as H2O2 and the nitric oxide radical (NO•),4 which have been shown to play important roles as effector molecules in immune defence systems against pathogens, and as signalling molecules.5,6 For this reason, the elimination of all types of ROS through powerful antioxidant therapies is likely to disrupt important cellular functions. Indeed, it has been reported that radical suppression of oxidative stress can promote tumour progression.7 Nevertheless, overproduction of several types of ROS has been associated with a range of toxic effects. The majority of these effects have been associated with the hydroxyl radical •OH, one of the most reactive of the ROS species,8 which can indiscriminately damage cellular components including lipid, protein, carbohydrate and nucleic acid, ultimately leading to cellular necrosis and apoptosis. This raises the prospect of developing selective antioxidants that preferentially remove toxic radicals such as •OH, but not others (such as H2O2 or NO•).4 The accumulation of ROS is generally counterbalanced by a sophisticated endogenous antioxidant defence system that comprises enzymes – such as superoxide dismutase (SOD), catalase and glutathione peroxidase – and non-enzymes, such as vitamin A, vitamin C, carotene and bilirubin. Although O –• and H O can be Y Hong, S Chen, J-M Zhang Hydrogen as a selective antioxidant with unpaired electrons in an open shell configuration; these unpaired electrons make the radical species highly chemically reactive. ROS include superoxide anion (O –•), •OH cannot be detoxified by this route. This has emphasized the importance of antioxidants targeting •OH. Approximately 4000 antioxidants have been described to date, most of which are electron donors that react with ROS to form harmless end-products such as water. Although many have given promising results in animal models of oxidative stress, in most cases the beneficial effects seen in animal studies have not been reiterated in clinical trials.9 Barriers to the utilization of exogenous antioxidants include low membrane permeability and high toxicity, which constrain administration to a narrow window of therapeutic dosage.10 The identification of a novel and more effective antioxidant is, therefore, of high priority. Rationale behind H : a 2 selective antioxidant It has long been known that H2 – a colourless, odourless and tasteless gas – has antioxidant properties, but the potential exploitation of H2 as a therapeutic agent has only recently been explored in animal models and in the clinic. The first study, by Dole et al.11 reported that there was significant cancer regression in patients with squamous cell carcinoma exposed to hyperbaric H2 for 2 weeks. In 2001, hyperbaric H2 was reported to be beneficial in the treatment of schistosomiasis- associated chronic liver inflammation, and its therapeutic properties were ascribed to scavenging of •OH.12 These studies were not, however, extended by other researchers, perhaps in view of the explosion hazards associated with hydrogen. Nevertheless, it is important to note that such risks are eliminated when used in H2/air mixtures of < 4.6% (v/v).12 Ohsawa et al.13 studied the antioxidant properties of molecular H and 2222 detoxified by antioxidant defence enzymes, reported that it selectively reduces •OH and 1894

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