A hypothesis on chemical mechanism of the effect of hydrogen
© Shi et al.; licensee BioMed Central Ltd. 2012
Received: 23 May 2012
Accepted: 23 May 2012
Published: 21 June 2012
Many studies have shown that hydrogen can play important roles on the antioxidant, anti-inflammatory and other protective effects. Ohsawa et al have proved that hydrogen can electively and directly scavenge hydroxyl radical. But this mechanism cannot explain more new experimental results. In this article, the hypothesis, which is inspired by H2 could bind to the metal as a ligand, come up to explain its extensive biology effect: Hydrogen could regulate particular metalloproteins by bonding (M–H2 interaction) it. And then it could affect the metabolization of ROS and signal transduction. Metalloproteins may be ones of the target molecules of H2 action. Metal ions may be appropriate role sites for H2 molecules. The hypothesis pointed out a new direction to clarify its mechanisms.
Much evidence has shown that hydrogen exert beneficial effects in animal models of a number of diseases mainly associated with oxidative stress; However, the findings don’t cover plants. Moreover, the mechanism of the effect of hydrogen remains unclear, the most acceptable mechanism is that the hydrogen can electively and directly scavenge hydroxyl radical while preserving other reactive oxygen and nitrogen species important in signaling . There is some question, however, the published rate constant for the reaction of ·OH with H2 to form H2O and H· is drastically slower than most radical-radical reactions . Furthermore, it can’t explain some new experimental results. For example, Tomohiro Itoh proved that hydrogen exerts its beneficial effect by modulating some signaling pathways. Experimenters found that oral intake of hydrogen-rich water abolishes an immediate-type allergic reaction in mice. The results indicated that hydrogen attenuates phosphorylation of the FcεRI-associated Lyn and its downstream signal transduction, which subsequently inhibits the NADPH oxidase activity and reduces the generation of hydrogen peroxide. they also found that inhibition of NADPH oxidase attenuates phosphorylation of Lyn in mast cells, indicating the presence of a feed-forward loop that potentiates the allergic responses. Hydrogen accordingly inhibits all tested signaling molecule(s) in the loop. The results imply that effects of hydrogen in some diseases are possibly mediated by modulation of yet unidentified signaling pathways .
Hypothesis and discussion
Although the beneficial effect of hydrogen is generally accepted, the mechanism is not still clear. There can be little doubt that biology function of H2 depends on the physical and chemical interaction of other molecules with it , so what would it be like?
Iron-sulphur proteins in cells
Bacterial nitrate reductase, Formate dehydrogenase, Fumarate reductase, Glutamine PRPP amidotransferase, Hydrogenase, Methane monooxygenase, NADH:ubiquinone reductase, Phthalate dioxygenase reductase, Succinate dehydrogenase, Sulphite reductase, Xanthine dehydrogenase, Aconitase (TCA cycle)
Ferredoxins, Rieske proteins, Rubredoxins, NADH Dehydrogenase, Succinate-CoQ Reductase, CoQ-cyt c Reductase (respiratory chain complexes)
It is proved from experiments that molecules containing a metallic cation may promote O2− formation because they have the ability to store and easily give an electron to molecular dioxygen . Free radicals arise through the autoxidation catalyzed by metalloproteins, this mainly occurs within the mitochondria. Some experimental results proved that hydrogen can permeate into mitochondria and prevent superoxide formation . It indicates that H2 can affect the metabolization of ROS by way of superoxie formation. And it must have a big impact on the content of H2O2. Besides, free radical production can also happen in other cellular compartments, such as NADPH oxidase. ROS production can interfere with signal transduction pathways [18–20]. ROS, in particular H2O2, are indeed second messengers for many physiological stimuli, some stimuli have been proven to induce mitochondrial H2O2 release .
On the basis of the mentioned analysis, we evaluate that metal ions could be appropriate role sites for H2 molecules. We propose that hydrogen can permeate into mitochondria and concentrate at mitochondrial membrane to regulate activity of metalloproteins (complexesI,II,III) by M–H2 interaction. The same may be true of NADPH oxidase. This could reduce the production of superoxide and prevent synthesis of the hydroxyl from the source. Hydrogen, on the one hand, maybe regulate the content of H2O2 by affecting the metabolization of ROS. And then it disturbs signaling pathway. On the other hand, hydrogen maybe directly influence signal transduction by regulating particular metalloproteins of signaling pathways. It may be the mechanism of its extensive biology effect.
We propose that metalloproteins may be ones of the target molecules of H2 action. Metal ions may be appropriate role sites for H2 molecules. And in this way can we explain its extensive biology effect. Although some details remain murky, the hypothesis pointed out a new direction for the continuation. It is a good inspiration to clarify the mechanism of the effect of hydrogen. We predict that hydrogen can affect many metalloproteins activities.Therefore, more studies will be necessary to test the hypothesis.
We wish to sincerely thank Xuejun Sun (Second Military Medical University, Shanghai, China) for advice about the manuscript.
There is no source of support in the form of grants.
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