OXIDATIVE DAMAGE AND DHA
EPA and DHA are the most unsaturated fatty acids found in large quantities in the bodies of animals and therefore are likely to be more vulnerable to lipid peroxidation than any other fats. Early experiments showed that extremely high levels of cod liver oil in experimental animals can produce enough oxidative damage to result in muscle lesions. Subsequent experiments showed that these lesions can be prevented with vitamin E.
More recent and more careful studies have shown that the oxidative damage due to fish oil -- and the ability to protect against it -- varies greatly between tissues. Vitamin E is least able to protect against oxidation of either EPA or DHA in blood plasma. The alpha-tocopherol form of vitamin E protects red blood cell membranes of young animals more effectively than those of old animals. Although both alpha- and gamma-tocopherol protect against lipid peroxidation, they do so by different mechanisms. Generally, gamma-tocopherol is only 30% as effective as the alpha form as an anti-oxidant, but gamma-tocopherol is particularly effective against peroxynitrite.
Alpha-tocopherol protects against oxidative damage from fish oil far more effectively in the liver than in the kidney. But the kidney is less vulnerable to oxidative damage because kidney cell membrane composition is much less subject to alteration by changes in dietary fat. Although a four-fold increase in alpha-tocopherol above normal dietary levels has been shown to reduce fish oil-induced peroxidation in monkey livers, peroxidation was not completely eliminated. The experimenters suggested that higher levels of vitamin E or other anti-oxidants might reduce the damage further.
Oxidative damage to the heart due to fish oil, however, is much less than oxidative damage to the liver or even the kidney. When incorporated into heart muscle membranes, both EPA and DHA promote alpha-tocopherol being incorporated into the membranes as well. In fact, a high omega-3 fatty acid diet increases the alpha-tocopherol content of heart muscle membranes by five times, and this effect is most prominently associated with DHA.
Vitamin E provides more anti-oxidant benefit to the heart and spleen than selenium, beta-carotene or coenzyme Q10. In fact, at the maximum effective dose of Vitamin E, the other anti-oxidants offer no additional benefit. Selenium, however, gives the most anti-oxidant protection to the kidney. Under certain oxidative stresses coenzyme Q10 gives the most protection to the liver, with little additional benefit from the other anti-oxidants.
DHA's most remarkable effect on oxidation is in the brain, where increasing tissue levels of DHA in the cerebral cortex causes significant increases in the anti-oxidant enzymes catalase, glutathione and glutathione peroxidase -- resulting in decreased cerebral levels of lipid peroxides. The induction of anti-oxidant enzymes by DHA in the brain is so dramatic that the researchers actually referred to DHA as an anti-oxidant. Although DHA is more readily oxidized than arachidonic acid, arachidonic acid breakdown products (endoperoxides & eicosanoids) generate more free radicals than the products of DHA. DHA also inhibits inhibits inducible nitric oxide synthetase (reducing formation of the peroxynitrite free radical) and inhibits transcription factor NF-KappaB (reducing formation of pro-inflammatory cytokines) [FREE RADICAL BIOLOGY AND MEDICINE 34(8):1006-1016 (2003)].
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