Mutant organisms that lack these repair enzymes are

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DNA to its original, undamaged state. Mutant organisms that lack these repair enzymes are found to be hypersensitive to O 2 , H 2 0 2 , or other oxidants. 6 One particularly interesting aspect of oxidant stress is that most aerobic organisms can survive in the presence of normally lethal levels of oxidants if
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III. DIOXYGEN TOXICITY 265 they have first been exposed to lower, nontoxic levels of oxidants. This phe- nomenon has been observed in animals, plants, yeast, and bacteria, and suggests that low levels of oxidants cause antioxidant systems to be induced in vivo. In certain bacteria, the mechanism of this induction is at least partially understood. A DNA-binding regulatory protein named OxyR that exists in two redox states has been identified in these systems. 33 Increased oxidant stress presumably in- creases concentration of the oxidized form, which then acts to turn on the tran- scription of the genes for some of the antioxidant enzymes. A related phenom- enon may occur when bacteria and yeast switch from anaerobic to aerobic metabolism. When dioxygen is absent, these microorganisms live by fermenta- tion, and do not waste energy by synthesizing the enzymes and other proteins needed for aerobic metabolism. However, when they are exposed to dioxygen, the synthesis of the respiratory apparatus is turned on. The details of this induc- tion are not known completely, but some steps at least depend on the presence of heme, the prosthetic group of hemoglobin and other heme proteins, whose synthesis requires the presence of dioxygen. 34 D. Molecular Mechanisms of Dioxygen Toxicity What has been left out of the preceding discussion is the identification of the species responsible for oxidative damage, i.e., the agents that directly attack the various vulnerable targets in the cell. They were left out because the details of "- the chemistry responsible for dioxygen toxicity are largely unknown. In 1954, Rebeca Gerschman formulated the "free-radical theory of oxygen toxicity" after noting that tissues subjected to ionizing radiation resemble those exposed to elevated levels of dioxygen. 35 Fourteen years later, Irwin Fridovich proposed that the free radical responsible for dioxygen toxicity was superoxide, O 2 , based on his identification of the first of the superoxide dismutase enzymes. 36 Today it is still not known if superoxide is the principal agent of dioxygen toxicity, and, if so, what the chemistry responsible for that toxicity is. 6 There is no question that superoxide is formed during the normal course of aerobic metabolism,121 although it is difficult to obtain estimates of the amount under varying conditions, because, even in the absence of a catalyst, superoxide disproportionates quite rapidly to dioxygen and hydrogen peroxide (Reaction 5.4) and therefore never accumulates to any great extent in the cell under normal conditions of pH.
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