Pathophysiological Conditions For Freeradical Generation In Biological Systems

Some of the pathophysiological conditions for free-radical generation in biological systems are described in the following subsections.

FIGURE 13.1 Reaction mechanisms for generation of ROS and RNS in the cellular environment.

13.2.1.1 Leakage from Damaged Mitochondrial Chain

The mitochondrial electron transport chain reduces oxygen to water, where oxygen is reduced by accepting four electrons, leading to the formation of two water molecules. However, upon mitochondrial damage, a variable fraction of electrons can leak from the mitochondrial chain, leading to the univalent reduction of molecular oxygen, which n * o *

generates ; The s dismutates to H202 in a reaction catalyzed by superoxide dismutase. H2O2 can spontaneously but very slowly form OH- and OH, a process that is greatly enhanced by the presence of transition metals such as Fe2+.16

13.2.1.2 Reactions Involving Iron and Other Transition Metals

Under inflammation and other infectious conditions, the intracellular pool of active transition metal ions is released, which causes ROS generation by Haber-Weiss reaction. Apart from Fe, other metal ions such as Cu, Cr, Co, and Ni also catalyze this reaction, resulting in the formation of ^OH radicals.17

13.2.1.3 Ischemia/Reperfusion

Ischemia reperfusion (I/R),17-22 or the temporary interruption of blood supply to an organ followed by resumption of blood flow, causes ROS production primarily from the xanthine oxidase pathway. In tissues, hypoxanthine is metabolized by xanthine dehydrogenase, which uses NADH as the electron acceptor. However, xanthine oxidase is generated during anoxia from xanthine dehydrogenase by proteases activated due to elevated Ca2+ levels. Further, the decreased adenosine triphosphate (ATP) synthesis with ischemia is manifested by dephosphorylation of adenosine diphosphate (ADP) to adenosine monophosphate (AMP), which is degraded to adenosine, inosine, and hypoxanthine. With reperfusion, hypoxanthine provides the substrate for xanthine oxidase to use 02 as an electron acceptor, leading to the formation of superoxide ) and, following its dismutation, H2O2. These products can react, especially in the presence of transition metals such as Fe2+, to produce the hydroxyl radical OOH). Another route of ROS production during I/R is the NADPH oxidase pathway where, with the decreased shear shows with ischemia, membrane depolarization occurs, resulting in assembly of the NADPH oxidase subunit, thus leading to ROS generation.20-22

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