Fatty acids oxidative stress

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). 

Biochemical stress can be minimized by using frequent feedings to minimize dependence on fatty acid oxidation, particularly for the liver. Meals should have a high-carbohydrate, low-fat content. Medium-chain triglycerides (synthetic or derived from coconut or palm kernel oils) can be used as these lipids can be oxidized independent of carnitine. These steps are particularly important when any external metabolic stress, such as a viral illness, is present. 

In this study, the analysis of plasma samples from patients suffering from fatty acid oxidation defects or organic acidemias (n = 103) showed abnormal acyl-camitine profiles in all cases when the samples were taken under stress (e.g. hypoglycemic episodes). In clinically stable episodes an essentially normal acyl-camitine profile was obtained for only one patient with a mild form of SCAD deficiency and for a patient with a mild form of multiple acyl-CoA dehydrogenase deficiency (data not shown). For all other defects abnormal profiles were observed under a wide variety of clinical conditions illustrating the high sensitivity of the method. In table 2, the upper reference limit, defined as the... 

If the direct feedback link is strong, so that the flux is very sensitive to regulators of the tricarboxylic acid cycle, the flux will not be sensitive to changes in extracellular fatty acid concentration, resulting from increased mobilization from the adipose tissue reserves. This would be unfortunate since the extracellular fatty acid concentration is an important signal for tissues to increase their rate of fatty acid oxidation when carbohydrate stores are being depleted (carbohydrate stress). However, if a branch point exists at the level of acetyl-CoA, the resulting branched system provides feedback indirectly, as discussed in Section II. [Such a branch could be the pathway that produces ketone bodies (in the liver) or deacylation to acetate which may occur in some tissues—see Knowles et al. (28) and Buckley and Williamson (6). ... 

These include the mitochondrial respiratory chain, key enzymes in fatty acid and amino acid oxidation, and the citric acid cycle. Reoxidation of the reduced flavin in oxygenases and mixed-function oxidases proceeds by way of formation of the flavin radical and flavin hydroperoxide, with the intermediate generation of superoxide and perhydroxyl radicals and hydrogen peroxide. Because of this, flavin oxidases make a significant contribution to the total oxidant stress of the body. 

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