Functions and physiological significance of vitamin E in humans
Although there is little disagreement among investigators about the general protective role of vitamin E in the cellular and subcellular membrane structures, there is little agreement about the mechanism by which the specific function of vitamin E as an essential nutrient is carried out. Three major theories have been advanced. Tappel makes a strong case for the lipid antioxidant theory, which suggests that vitamin E is a physiological antioxidant protecting the polyunsaturated fatty acids and other easily oxidizable essential components of the body structure and function against peroxidative damage by internal and external insults. According to the respiratory chain hypothesis, vitamin E has a specific catalytic role in electron transport through the mitochondrial respiratory chain. The genetic regulation hypothesis postulates that vitamin E exerts control over the transfer of genetic information in the cells.
Although many arguments have been raised against the antioxidant theory,61 evidence has accumulated to indicate that vitamin E is part of a multilevel cellular defense system that protects susceptible structures against oxidative damage by lipid peroxidation. It is now believed that lipid peroxidation is initiated by a hydroxyl-free radical (OH) which is produced from a reaction behveen superoxide (0-2) and hydrogen peroxide (H202) both products of normal cellular metabolismY In an unprotected cell these free radicals attack membrane lipids at the double bonds of the polyunsaturated fatty acids and form lipid peroxide radicals, which propagate chain reactions along the membrane and form lipid hydroperoxides at each double bond left behind. Unless stabilized, further oxidative degradation of these hydroperoxides results in damage to the membrane.
In a normal cell, first line defense is provided by sequential reactions that remove 0-2 and H202 thereby reducing the substrates available for free radical formation. As discussed, the joint action ofsuperoxide dismutases (zinc-, copper- and manganese-containing enzymes in the mitochondria and cytoplasm, respectively) and the selenium-containing glutathione peroxidase (GSH-Px) results in the reduction of 0- 2 and H202 to water. Reduced glutathione (GSH), a cysteine-containing tripeptide, is the source of reducing equivalents in the degradation ofH202 and must be continuously replenished (reaction I -3) .
The second line of defense is provided at the membrane site of peroxidation by vitamin E and GSH-Px. Vitamin E molecules, stationed among the membrane lipids, reduce the advancing peroxide radicals within their reach and stop the chain reactions. GSH-Px reduces the hydroperoxides as they are formed and, by formation of hydroxy fatty acids, stabilizes the membrane against autoxidative degradation. Scott and co-workers have demonstrated that protection against peroxidation of mitochondrial and microsomal lipids is dependent on the presence of vitamin E in the membranes and GSHPx in the soluble cell fraction and required GSH.
It has not been possible to measure lipid peroxidation in vivo until the recent introduction of a new experimental technique that employs the measurement of volatile oxidation products of polyunsaturated fatty acid (PUFA) in the expired air collected from intact animals (ethane and pentane gases from linolenic and linoleic acids, respectively). With this method several investiga tors have demonstrated in vivo lipid peroxidation in rats fed diets deficient in vitamin E, selenium, and sulfur-containing amino acids, and observed variable protective effects from supplementation with each individually or in combinations. Feeding cod-liver oil or corn oil in place oflard greatly increased lipid peroxidation when measured by this method. In rats fed cod-liver oil, selenium supplementation reduced ethane production by half, while vitamin E supplementation reduced it to almost zero.
Although specific catalytic or hormone-like functions proposed for vitamin E have not been ruled out by these findings, it is possible that the effects of vitamin E observed in numerous enzyme systems or individual enzymes are the result of alterations in membrane structure and permeability which in turn are intricately linked to the normal functioning of the major systems that are responsible for cellular metabolism.
There is strong agreement among the investigators that the need for vitamin E is related to the amount of polyunsaturated fatty acids in the tissues. Red blood cells from subjects on low vitamin E and high polyunsaturated fatty acid dietary intakes have less resistance to hemolysis in the presence of hydrogen peroxide than those from subjects on higher vitamin E and lower PUFA intakes. Although the clinical significance is not clear, this test is one of the measure men ts used to determine the vitamin E status of individuals. Vitamin E deficiencies in man are very rare; however, considerable interest has been shown in this area because of the relationship of vitamin E to PUFA and the present trend toward increasing PUFA in the diets oflarge segments of the population.
There are some special condi tions in which inadequate vitamin E status may develop. This has been most clearly demonstrated in premature infants, who have low plasma vitamin E levels because of its poor transfer across the placenta; immaturity of the intestine reduces the absorption of dietary vitamin E. As a result, vitamin E deficiency syndrome characterized by hemolytic anemia, edema, and skin lesions may develop, especially if the infant is fed a formula high in PUF A.Effectiveness of oral vitamin E supplementation increases with gestational age supplementation with iron alone has been shown to aggravate the anemia by acting as a pro-oxidant and by further reducing the absorption of vitamin E.
Vitamin E supplementation in premature infants also has been reported to decrease the incidence of retrolental fibroplasia and chronic bronchopulmonary dysplasia. Adequa te vitamin E status may be important in protecting the lungs against oxidative damage in patients receiving pure 0247 and against damage by air pollutants, such as ozone (03) and nitrous oxide (N02).
In a long-terme APeriment to study vitamin E deficiency in humans, low plasma tocopherol levels, increased susceptibility of erythrocytes to peroxide-induced hemolysis, and slightly decreased erythrocyte survival time were the only changes observed in male subjects ingesting approximately 3 mg a-tocopherol per day over 6 yearsY Supplementation with vitamin E showed a small but significant increase in r,eticulocytes. Decreased erythrocyte survival time and correction by vitamin E also has been reported in patients with cystic fibrosis and other conditions in which low plasma vitamin levels are found secondary to in testinal malabsorption. Inefficient erythropoiesis has been observed in vitamin E-deficient monkeys, which also had anemia and decreased erythrocyte survival. Treatment with a-tocopherol acetate corrected all abnormalities. It appears that anemia in vitamin E deficiency may result from the combined effects of increased hemolysis and inefficient erythropoiesis.
The hematopoietic effect of vitamin E on children with protein-calorie malnutrition is not clear because different workers report varying results from the administration of this vitamin.
Increased creatinuria, presumed to reflect muscle breakdown, has been observed in both children and adults ,with cystic fibrosis and in premature infants reduction in creatinuria followed vitamin E supplementation.
