Edited 24 August 2012

Pharmacological activity of molecular hydrogen (central focus on relationship with reactive oxygen)

1. Introduction
 According to recent study results of gaseous molecules, various physiologic activities have been seen of gaseous molecules of nitric oxide (NO), carbon monoxide (CO), hydrogen sulfide (H2S) and hydrogen (H2) within a living body. Here, we will give an overview of the pharmacological activity of molecular hydrogen particularly with a central focus on its relationship with reactive oxygen.
2. Properties of hydrogen
 Hydrogen is the element constituting matter most found in the universe, however, there is only a minute trace of 1 ppm or less in the air.  Molecular hydrogen (H2) is the lightest gaseous molecule, colorless and odorless, and easily burnable at normal temperature.  Moreover, hydrogen dissolves into water up to a concentration of 1.6 ppm wt/vol under normal pressure, but easily escapes from glass and plastic containers.
 On the other hand, hydrogen is always produced in our bodies through the process of fermenting indigestible dietary fiber by intestinal bacteria. Inhalation of hydrogen gas has been used for treatment of caisson disease until now and has demonstrated to be extremely safe.
3. Super saturated hydrogen generating apparatus (‘hydrogen water 7.0’)
 The solubility of molecular hydrogen (H2) into water under normal temperature and pressure is 1.6 ppm wt/vol as mentioned above; however, super saturated molecular hydrogen (H2) can be added to water up to 5 ppm wt/vol by installing a super saturated hydrogen generating apparatus in a beverage container such as a plastic bottle, making a hydrogen generating agent react, and applying pressure. This hydrogen generating agent is constituted by authorized components as food additives without including metal magnesium, and does not directly make contact with the water in the plastic bottle, and is thus very safe. The chemical formula for hydrogen generation of this hydrogen generating agent is as follows.
4. Reactive oxygen and free radical
 Oxidation is one of the activities of oxygen. Even in our bodies, part of the oxygen we breathe becomes active oxygen and oxidizes cells, leading to many diseases such as cancer and atherosclerosis.
 All matter is made from molecules. A molecule is the smallest unit constituting matter, having a nucleus and negatively, electrically charged electrons circuiting around a nucleus. While a pair of two electrons is normally accommodated in a single orbit, there are cases where only one electron exists in an orbit depending on the type of molecule. An atomic element or molecule having such an ‘unpaired electron’ is called a free radical.
 Fundamentally, electrons are in a most stable state when paired in an orbit. As a result, the free radical is unstable, and tries to take an electron from another molecule in order to become stable. The free radical is an atomic element or molecule that has extremely high reactivity since it has one or more unpaired electrons. The matter from which an electron has been taken by the free radical is thereby oxidized.
5. Documents on hydrogen
 Ota et al reported in the 2007 edition of Nature Medicine that hydrogen containing gas can effectively eliminate hydroxyl radical (•OH), which is reactive oxygen, thereby reducing damage after cerebral ischemia. That is, when cerebral ischemia reperfusion disorder is conduced in rats so as to produce a large quantity of reactive oxygen were given 1 to 4% hydrogen gas to inhale, it was clear that damage of the brain was reduced.
 This report by Ota et al shows that molecular hydrogen (H2) eliminates •OH, which has the strongest cell damaging activity among reactive oxygen species (ROS), but does not eliminate superoxide (O2) or hydrogen peroxide (H2O2) that contribute to cellular functions. The scheme for •OH production and •OH elimination by hydrogen is given below.
 The oxygen we intake through breathing produces O2 through the process of generating energy. The normal oxygen molecule has sixteen electrons, but O2 has seventeen electrons, where one of them is an unpaired electron, and is a free radical. O2 becomes H2O2 due to the SOD within our bodies, and H2O2 is converted into H2O and O2 due to catalase and GPX, thereby being detoxified. However, a part of the O2 and H2O2 react with ferric ions and copper ions, producing •OH. Fundamentally, transition metals such as iron and copper exist by coupling with proteins; however, in inflamed regions, these transition metals exist as ions and produce a large quantity of •OH. •OH also has an unpaired electron, and its oxidizing power is strongest in reactive oxygen.
6. Internalization of molecular hydrogen (H2)
 Unlike other antioxidants, molecular hydrogen (H2) easily passes through cell membrane and taken into mitochondria and nuclei, thereby exhibiting a protection effect on mitochondria and nucleus DNA. Through this internalization and protection effect of molecular hydrogen (H2) on organelle, preventive effect of hydrogen (H2) on lifestyle diseases, cancer, and aging contributed by damage of mitochondria and nucleus DNA is expected.
7. Pharmacological activity of molecular hydrogen (H2)
 Several hydrogen gas applying methods have been reported. For example, there are methods such as hydrogen gas inhalation, oral ingestion of water (hydrogen-rich water) in which hydrogen gas is dissolved, hydrogen water chemical bath, injection or application of eye drops of physiologic saline in which hydrogen gas is dissolved, increasing hydrogen production by intestinal bacteria that produces hydrogen (e.g., oral administration of lactulose or oligosaccharide). Ever since medicinal benefits of the antioxidant effect of molecular hydrogen (H2) was first described in Nature Medicine in 2007, there have been numerous reports of the physiological activity and clinical effects of molecular hydrogen (H2). From recent study results, molecular hydrogen (H2) shows not only an antioxidant effect, but also anti-inflammatory effect, anti-allergic activity, anti-apoptotic activity, and lipid metabolism stimulating activity, as are given below. In addition, it has been demonstrated that molecular hydrogen (H2) shows inhibitory effects on cell injury by oxidative stress with concentration-dependency (Murakami et al, 2013).
7.1 Results of animal test
① Inhalation of hydrogen gas
     ・Preventive effect on ischemia reperfusion disorder of rats having cerebral infarction
     ・Preventive effect on ischemia reperfusion disorder of the liver or heart
     ・Protection effect on organ transplantation
     ・Effective for infectious diseases (septicemia)
     ・Anti-inflammatory effect
     ・Anti-apoptotic action
② Oral ingestion of hydrogen gas
     ・Preventive effect on cognitive deterioration
     ・Preventive and therapeutic effect on Parkinson’s disease models
     ・Preventive effect on atherosclerosis models
     ・Improvement effect on metabolic syndrome
     ・Side effects preventive effect on antitumor medicine (Cisplatin)
     ・Antiallergic action
     ・Effective for organ transplantation
③ Injection of hydrogen saturated physiologic saline (intraperitoneal injection)
     ・Effective for neonatal hypoxic ischemia rat models
     ・Effective for Alzheimer’s disease mouse models
④ Direct application
     ・Improvement effect on glaucoma models (instillation of eye drops)
     ・Absorption from the skin in a chemical bath
7.2 Results of clinical test
     ・Effective for cerebral infarction
     ・Preventive effect on side effects for radiotherapy
     ・Effective for rheumatoid arthritis
     ・Effective for chemical bath or application to the skin
     ・Improvement effect on type 2 diabetes
     ・Improvement effect on metabolic syndrome
8. Safety of molecular hydrogen
 An in vitro mutation test and gene toxicity test on a hydrogen solution and a subchronic toxicity test using rats were conducted, finding statistical significant differences in a part of the items in the subchronic toxicity test. However, these significant differences were seen in change with the one side sex group and change within normal limits, and thus biological significant difference is impossible. While changes were seen even in humans in similar subchronic toxicity tests, it was all change within normal limits.
 Judging comprehensively from these animal tests, tests on humans, and cases of long use of hydrogen gas in treatment for caisson disease, safety of molecular hydrogen (H2) was extremely high.
9. References
Ikuroh Ohsawa, Masahiro Ishikawa, Kumiko Takahashi, Megumi Watanabe, Kiyomi Nishimaki, Kumi Yamagata, Ken-ichiro Katsura, Yasuo Katayama, Sadamitsu Asoh and Shigeo Ohta (2007):Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nature Medicine, 13:688-694.
Chien-Sheng Huang, Tomohiro Kawamura, Yoshiya Toyoda and Atsunori Nakao (2010):Recent Advances in Hydrogen Research as a Therapeutic Medical Gas. Free Radical Research, 44:971-982.
Shigeo Ohta(2011):Recent Progress Toward Hydrogen Medicine: Potential of Molecular Hydrogen for Preventive and Therapeutic Applications. Current Pharmaceutical Design, 17:2241-2252.
Yayoi Murakami and Ikuroh Ohsawa(2013):OS-9, Inhibitory effects of molecular hydrogen on oxidative stress mediated by Nrf2, p53, The proceeding of 3th Symposium of Medical Molecular Hydrogen.
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