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Hydrogen Peroxide Metabolism In Health And Disease !NEW!

Much of the biology of oxidative stress and oxidative signalling centres on the generation and handling of hydrogen peroxide. The overall aim for this book would be to provide an insightful and useful forum to assist with the understanding of the relevance of hydrogen peroxide generation and how this is managed in human biology. The target audience would be those who currently have an interest in the generation of ROS, but who do not have expertise in chemistry, as well as those experts in the chemistry of oxidative stress, but without detailed understanding of the biologically relevant setting. We would aim to bridge the gap in understanding between chemistry and biology.

Hydrogen Peroxide Metabolism in Health and Disease


Hydrogen peroxide (H2O2), a non-radical reactive oxygen species generated during many (patho)physiological conditions, is currently universally recognized as an important mediator of redox-regulated processes. Depending on its spatiotemporal accumulation profile, this molecule may act as a signaling messenger or cause oxidative damage. The focus of this review is to comprehensively evaluate the evidence that peroxisomes, organelles best known for their role in cellular lipid metabolism, also serve as hubs in the H2O2 signaling network. We first briefly introduce the basic concepts of how H2O2 can drive cellular signaling events. Next, we outline the peroxisomal enzyme systems involved in H2O2 metabolism in mammals and reflect on how this oxidant can permeate across the organellar membrane. In addition, we provide an up-to-date overview of molecular targets and biological processes that can be affected by changes in peroxisomal H2O2 metabolism. Where possible, emphasis is placed on the molecular mechanisms and factors involved. From the data presented, it is clear that there are still numerous gaps in our knowledge. Therefore, gaining more insight into how peroxisomes are integrated in the cellular H2O2 signaling network is of key importance to unravel the precise role of peroxisomal H2O2 production and scavenging in normal and pathological conditions.

Although these genetic factors influence drinking patterns, environmental factors also are important in the development of alcoholism and other alcohol-related health consequences. For example, Higuchi and colleagues (17) found that as alcohol consumption in Japan increased between 1979 and 1992, the percentage of Japanese alcoholics who carried the protective ADH1B*2 gene version increased from 2.5 to 13 percent. Additionally, despite the fact that more Native American people die of alcohol-related causes than do any other ethnic group in the United States, research shows that there is no difference in the rates of alcohol metabolism and enzyme patterns between Native Americans and Whites (18). This suggests that rates of alcoholism and alcohol-related problems are influenced by other environmental and/or genetic factors.

Researchers continue to investigate the reasons why some people drink more than others and why some develop serious health problems because of their drinking. Variations in the way the body breaks down and eliminates alcohol may hold the key to explaining these differences. New information will aid researchers in developing metabolism-based treatments and give treatment professionals better tools for determining who is at risk for developing alcohol-related problems.

In the late 1980s the first hydrogen peroxide gas plasma system for sterilization of medical and surgical devices was field-tested. According to the manufacturer, the sterilization chamber is evacuated and hydrogen peroxide solution is injected from a cassette and is vaporized in the sterilization chamber to a concentration of 6 mg/l. The hydrogen peroxide vapor diffuses through the chamber (50 minutes), exposes all surfaces of the load to the sterilant, and initiates the inactivation of microorganisms. An electrical field created by a radio frequency is applied to the chamber to create a gas plasma. Microbicidal free radicals (e.g., hydroxyl and hydroperoxyl) are generated in the plasma. The excess gas is removed and in the final stage (i.e., vent) of the process the sterilization chamber is returned to atmospheric pressure by introduction of high-efficiency filtered air. The by-products of the cycle (e.g., water vapor, oxygen) are nontoxic and eliminate the need for aeration. Thus, the sterilized materials can be handled safely, either for immediate use or storage. The process operates in the range of 37-44C and has a cycle time of 75 minutes. If any moisture is present on the objects the vacuum will not be achieved and the cycle aborts.856, 881-883

Penetration of hydrogen peroxide vapor into long or narrow lumens has been addressed outside the United States by the use of a diffusion enhancer. This is a small, breakable glass ampoule of concentrated hydrogen peroxide (50%) with an elastic connector that is inserted into the device lumen and crushed immediately before sterilization.470, 885 The diffusion enhancer has been shown to sterilize bronchoscopes contaminated with Mycobacteria tuberculosis.886 At the present time, the diffusion enhancer is not FDA cleared.

Another gas plasma system, which differs from the above in several important ways, including the use of peracetic acid-acetic acid-hydrogen peroxide vapor, was removed from the marketplace because of reports of corneal destruction to patients when ophthalmic surgery instruments had been processed in the sterilizer.887, 888 In this investigation, exposure of potentially wet ophthalmologic surgical instruments with small bores and brass components to the plasma gas led to degradation of the brass to copper and zinc.888, 889 The experimenters showed that when rabbit eyes were exposed to the rinsates of the gas plasma-sterilized instruments, corneal decompensation was documented. This toxicity is highly unlikely with the hydrogen peroxide gas plasma process since a toxic, soluble form of copper would not form (LA Feldman, written communication, April 1998).

This process inactivates microorganisms primarily by the combined use of hydrogen peroxide gas and the generation of free radicals (hydroxyl and hydroproxyl free radicals) during the plasma phase of the cycle.

Materials and devices that cannot tolerate high temperatures and humidity, such as some plastics, electrical devices, and corrosion-susceptible metal alloys, can be sterilized by hydrogen peroxide gas plasma. This method has been compatible with most (>95%) medical devices and materials tested.884, 894, 895

Peroxisomes contain oxidative enzymes, such as D-amino acid oxidase and uric acid oxidase.[17] However the last enzyme is absent in humans, explaining the disease known as gout, caused by the accumulation of uric acid. Certain enzymes within the peroxisome, by using molecular oxygen, remove hydrogen atoms from specific organic substrates (labeled as R), in an oxidative reaction, producing hydrogen peroxide (H2O2, itself toxic):

Peroxisomes interact with mitochondria in several metabolic pathways, including β-oxidation of fatty acids and the metabolism of reactive oxygen species.[5] Both organelles are in close contact with the endoplasmic reticulum (ER) and share several proteins, including organelle fission factors.[32] Peroxisomes also interact with the endoplasmic reticulum (ER) and cooperate in the synthesis of ether lipids (plasmalogens) which are important for nerve cells (see above). In filamentous fungi, peroxisomes move on microtubules by 'hitchhiking,' a process involving contact with rapidly moving early endosomes.[33] Physical contact between organelles is often mediated by membrane contact sites, where membranes of two organelles are physically tethered to enable rapid transfer of small molecules, enable organelle communication and are crucial for coordination of cellular functions and hence human health.[34] Alterations of membrane contacts have been observed in various diseases.

In conclusion, men with abdominal obesity featured superoxide dismutase induction, and H2O2 accumulation in the visceral fat depot, despite upregulation of catalase activity. H2O2 concentrations, and superoxide dismutase and catalase activities in visceral fat correlated positively with HOMA-IR. This data in humans supports animal studies implicating dysregulated adipose tissue H2O2 metabolism in peripheral insulin resistance.

Vitamin C is required for the biosynthesis of collagen, L-carnitine, and certain neurotransmitters; vitamin C is also involved in protein metabolism [1,2]. Collagen is an essential component of connective tissue, which plays a vital role in wound healing. Vitamin C is also an important physiological antioxidant [3] and has been shown to regenerate other antioxidants within the body, including alpha-tocopherol (vitamin E) [4]. Ongoing research is examining whether vitamin C, by limiting the damaging effects of free radicals through its antioxidant activity, might help prevent or delay the development of certain cancers, cardiovascular disease, and other diseases in which oxidative stress plays a causal role. In addition to its biosynthetic and antioxidant functions, vitamin C plays an important role in immune function [4] and improves the absorption of nonheme iron [5], the form of iron present in plant-based foods. Insufficient vitamin C intake causes scurvy, which is characterized by fatigue or lassitude, widespread connective tissue weakness, and capillary fragility [1,2,4,6-9].

Due to its function as an antioxidant and its role in immune function, vitamin C has been promoted as a means to help prevent and/or treat numerous health conditions. This section focuses on four diseases and disorders in which vitamin C might play a role: cancer (including prevention and treatment), cardiovascular disease, age-related macular degeneration (AMD) and cataracts, and the common cold.

Emerging research suggests that the route of vitamin C administration (intravenous vs. oral) could explain the conflicting findings [1,46,47]. Most intervention trials, including the one conducted by Moertel and colleagues, used only oral administration, whereas Cameron and colleagues used a combination of oral and intravenous (IV) administration. Oral administration of vitamin C, even of very large doses, can raise plasma vitamin C concentrations to a maximum of only 220 micromol/L, whereas IV administration can produce plasma concentrations as high as 26,000 micromol/L [47,48]. Concentrations of this magnitude are selectively cytotoxic to tumor cells in vitro [1,67]. Research in mice suggests that pharmacologic doses of IV vitamin C might show promise in treating otherwise difficult-to-treat tumors [49]. A high concentration of vitamin C may act as a pro-oxidant and generate hydrogen peroxide that has selective toxicity toward cancer cells [49-51]. Based on these findings and a few case reports of patients with advanced cancers who had remarkably long survival times following administration of high-dose IV vitamin C, some researchers support reassessment of the use of high-dose IV vitamin C as a drug to treat cancer [3,47,49,52]. 041b061a72


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