Free radical reactive intermediates damage

Mitochondria are also involved in the cell s response to oxidative stress. As we have seen, several steps in the path of oxygen reduction in mitochondria have the potential to produce highly reactive free radicals that can damage cells. The passage of electrons from QH2 to cytochrome bL through Complex III, and passage of electrons from Complex I to QH2, involve the radical Q as an intermediate. The Q can, with a low probability, pass an electron to 02 in the reaction... 

Oxygen free radicals are required intermediates in many biological reactions but may damage macromolecules during oxidative stress 566 Reactive oxygen species generated during ischemia—reperfusion contribute to the injury 567... 

Free radical intermediates or other reactive intermediates may donate electrons to oxygenforming active oxygen species such as superoxide anion radical, O2 -, which can cause cellular damage (see above). 

Thus, the susceptibility is the result of accumulation of the drug in the target organ to reach concentrations not achieved in other tissues. This is then followed by what is probably a combination of events such as formation of a reactive intermediate, possibly a free radical, stimulation of lipid peroxidation and depletion of GSH, and then peroxidative damage to cell membranes and mitochondria. Whether metabolic activation by cytochromes P-450, or chemical rearrangement, or reductive activation, or all the three are involved is not currently clear. 

This four-electron reduction of 02 involves redox centers that carry only one electron at a time, and it must occur without the release of incompletely reduced intermediates such as hydrogen peroxide or hydroxyl free radicals—very reactive species that would damage cellular components. The intermediates remain tightly... 

In cells, DNA is always surrounded by proteins (cf. Fig. 12.2). The attachment of proteins modifies the DNA damage by various effects hampering an easy access of free-radicals, protection by compaction and repair of some of the damage by electron/hydrogen-donation. On the other hand, it may even induce some DNA damage via reactive intermediates formed upon the reaction of free radicals with the proteins. For this reason, the structure of DNA in solution and in the cellular environment will also have to be addressed. 

The mechanisms underlying hepatotoxicity from halothane remain unclear, but studies in animals have implicated the formation of reactive metabolites that either cause direct hepatocellular damage (eg, free radical intermediates) or initiate immune-mediated responses. With regard to the latter mechanism, serum from patients with halothane hepatitis contains a variety of autoantibodies against hepatic proteins, many of which are in a trifluoroacetylated form. These trifluoroacetylated proteins could be formed in the hepatocyte during the biotransformation of halothane by liver drug-metabolizing enzymes. However, TFA proteins have also been identified in the sera of patients who did not develop hepatitis after halothane anesthesia. 

The damage to animal or plant cells and tissues caused by ROS is called oxidative stress, which is caused by an imbalance between the production of reactive oxygen and a biological system s ability to detoxify the reactive intermediates or repair the resulting damage. A particularly negative side of oxidative stress is the production of ROS, which includes free radicals. 

Lipids do not escape damage by reactive intermediates. Lipids are oxidized in number of ways. They may be oxidized enzymatically, or via free-radical interaction (enzyme independent), or they can also be oxidized in a free-radical-independent,... 

Furthermore other free radical induced processes, e.g. lipid peroxidation, produce reactive intermediates that may be important. Examples of such other lesions are for example malondialdehyde induced DNA damage and exocyclic DNA adducts [22]. 

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