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THE INERTNESS OF OXYGEN Oxygen035002.html
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In most textbooks, oxygen is shown as a diatomic molecule with two bonds between the oxygen atoms. This is an attractive presentation, from the viewpoint of the electron dot structures and electron pairing to form chemical bonds, but it is incorrect. In fact, at body temperature, O2 is a biradical, a molecule with two unpaired electrons (Fig. 35.1). These electrons have parallel spins and are unpaired. Since most organic oxidation reactions, e.g. the oxidation of an alkane to an alcohol or an aldehyde to an acid, are two-electron oxidation reactions, O2 is generally not very reactive. In fact, O2 is completely stable in the presence of H2, a strong reducing agent, until enough heat is provided to flip an O2 electron and initiate the combustion reaction. Once it is started, the combustion provides the heat needed to propagate the reaction, sometimes explosively.
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Figure 35.1 Structure of oxygen and reactive oxygen species (ROS). Oxygen is shown at the far left as the incorrect double-bonded diatomic form. This form, known as singlet oxygen, exists to a significant extent only at high temperature or in response to irradiation. The diradical is the natural, ground-state form of O2 at body temperature. ROS are partially reduced, reactive forms of oxygen. The first product is the anion radical, superoxide (O2), which is in equilibrium with the weak acid, hydroperoxyl radical (pKa ≈ 4.5). Reduction of superoxide yields hydroperoxide O2-2, in the form of H2O2. Reduction of H2O2 causes a hemolytic cleavage reaction that releases hydroxyl radical (OH) and hydroxide ion (OH-). Water is the end product of complete reduction of O2.
RADIOTHERAPY AND CHEMOTHERAPY
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Applications of reactive oxygen OxygenReact035002.html
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Exposure to radiation from nuclear explosions or accidents, or breathing or ingestion of radioactive elements, such as Strontium-90 or radon gas, produces a flux of ROS in the body, causing mutations in DNA. Radiation therapy uses a focused beam of high-energy electrons or γ-rays from an X-ray or Cobalt-60 source to destroy tumor tissue. The radiation produces a flux of hydroxyl radicals (from water) and organic radicals at the site of the tumor, oxidizing and destroying the DNA of the tumor cell. Irradiation of food is also used as a method of sterilization to destroy bacterial and viral contaminants or destroy insect infestations in order preserve food products during long-term storage.
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Metabolic reactions are conducted at body temperature, far below the temperature required to activate free oxygen. In biological redox reactions involving O2, the oxygen is activated by redox active metal ions, such as iron and copper. All enzymes that use O2 in vivo are metalloenzymes and, in fact, even the oxygen transport proteins, hemoglobin and myoglobin, contain iron in the form of heme. These metal ions provide one electron at a time to oxygen, activating O2 for metabolism. Because iron and copper, and sometimes manganeseView drug information and other ions, activate oxygen, these redox-active metal ions are present at very low (sub-micromolar) free concentrations in vivo. Normally, they are tightly sequestered in inactive form in storage or transport proteins, and they are locally activated at the active sites of enzymes where oxidation chemistry can be contained and focused on a specific substrate. Free redox-active metal ions are dangerous in biological systems because, in free form, they activate O2.
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ISCHEMIA/REPERFUSION INJURY
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A patient suffered a severe myocardial infarction, which was treated with tissue plasminogen activator, a clot-dissolving (thrombolytic) enzyme. During the days following hospitalization, the patient experienced palpitations, irregular rapid heartbeat, associated with weakness and faintness. The patient was treated with anti-arrhythmic agents.
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Comment. Ischemia, meaning limited blood flow, is a condition in which a tissue is deprived of oxygen and nutrients. There is growing evidence that damage to heart tissue occurs not during the hypoxic or ischemic phase, but during reoxygenation of the tissue. This type of damage occurs following coronary occlusion, transplantation, and cardiovascular surgery. It is generally accepted that ROS play a major role in reperfusion injury. When cells are deprived of oxygen, they must rely on anaerobic glycolysis and glycogen stores for ATP synthesis. NADH and lactate accumulate, and all of the components of the mitochondrial electron transport system are saturated with electrons, because they cannot be transferred to oxygen. The mitochondrial membrane potential is increased, and when oxygen is reintroduced, great quantities of ROS are rapidly produced, overwhelming the scavenging mechanisms. ROS flood throughout the cell, damaging membrane lipids, DNA and other vital cellular constituents, leading to necrosis. There is considerable research on the evaluation of antioxidant supplements to protect tissues prior to transplantation, during surgery and during recovery from ischemia.
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Figure 35.2 Oxidative stress: an imbalance between pro-oxidant and antioxidant systems. As described in this chapter, numerous factors contribute to the enhancement and inhibition of oxidative stress. AGE, advanced glycation end-product; CAT, catalase; GPx, glutathione peroxidase; MPO, myeloperoxidase.
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