Oxidative phosphorylation Stress

Stadtman, E.R., 2002. Importance of individuality in oxidative phosphorylation stress and aging. Free Radic Biol Med 33, 597-604. 

In addition to the foregoing, three further examples in this list (numbers 5-7) deserve consideration. These are (5) interaction of endocrine disrupters with the estrogen receptor, (6) the action of uncouplers of oxidative phosphorylation, and (7) mechanisms of oxidative stress. Until now only the first is well represented by biomarker assays that have been employed in ecotoxicology. 

Critical for predictivity in a recent comprehensive study was the number and choice of parameters measured [4]. Early, sublethal effects on cell proliferation, cell morphology and mitochondria occurred consistently and ubiquitously with toxicity and when used collectively were most diagnostic. It is noteworthy that the toxicity of many drugs is attributable to various mitochondrial targets, including oxidative phosphorylation, fatty acid oxidation, Krebs cycling, membrane transport, permeability transition pore, proliferation and oxidative stress (Table 14.4). 

Oxidative stress Glutathione depletion (e.g., acetaminophen, bromoben-zene, chloroform, allyl alcohol) redox cyclers (see oxidative phosphorylation) reactive metabolites... 

The involvement of oxidative stress in AD has opened a new door for potential therapeutic targets. In this regard, several antioxidants are currently in clinical trials such as Idebenone, a-Lipoic acid, acetyl-L-carnitine (ALC), vitamin E, vitamin C, flavonoids, P-carotene, gingko biloba, and metal-chelating agents. Idebenone is a metabolic antioxidant and is normally synthesized as part of the mitochondrial oxidative phosphorylation system. Improvements in clinical status after treatment with idebenone have been shown in a dose-dependent manner compared to placebo and tacrine (Thai et al., 2003). 

DNP that uncouple oxidative phosphorylation (e.g., 4,6-dinitro-o-cresol) also increase the basal metabolic rate and cause weight loss in humans. Amphetamines and heat stress can also mimic the effects of 2,4-DNP. 

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