Vitamin E Deficiency in Experimental Animals

Vitamin E deficiency in experimental animals results in a number of different conditions, with considerable differences between different species in their susceptibility to different signs of deficiency. As shown in Table 4.2, some of the lesions can be prevented or cured by the administration of synthetic an-tioxidants, and others respond to supplements of selenium.

Vitamin E-deficient female animals suffer death and resorption of the fetuses. This was the basis of the original biological assay of the vitamin; female rats were maintained for 2 to 3 months on a vitamin E-free diet and then mated. Impregnation and implantation proceed normally; but, if they are not provided with vitamin E, the fetuses die and are resorbed. Five days alter mating, the animals were killed, and the number of surviving fetuses gave an index of the biological activity of the test compound, relative to standard doses of a-tocopherol. Synthetic antioxidants can replace vitamin E for this function, but selenium cannot.

Table 4.2 Responses of Signs of Vitamin E or Selenium Deficiency to Vitamin E, Selenium, and Synthetic Antioxidants in Experimental Animals

Vitamin E Selenium Synthetic Antioxidants

CNS, central nervous system.

Fetal resorption Testicular atrophy Necrotizing myopathy/white muscle disease CNS necrosis Exudative diathesis Erythrocyte hemolysis Liver necrosis Kidney necrosis

In male animals, deficiency results in testicular atrophy, with degeneration of the germinal epithelium of the seminiferous tubules. This lesion responds to vitamin E or selenium, but not to synthetic antioxidants.

Vitamin E deficiency results in the development of necrotizing myopathy, sometimes including cardiac muscle. This has been called nutritional muscular dystrophy, an unfortunate term, because deficiency of the vitamin is not a factor in the etiology of human muscular dystrophies, and supplements of the vitamin have no beneficial effect. The myopathy responds to selenium, but not to synthetic antioxidants.

The nervous system is also affected in deficiency, with the development of central nervous system necrosis (nutritional encephalomacia), a condition that can be exacerbated by feeding a diet especially rich in polyunsaturated fatty acids. There is also axonal dystrophy in animals maintained for prolonged periods of time on vitamin E-deficient diets. Synthetic antioxidants, but not selenium, can prevent these changes. The neuropathy begins from axonal membrane injury, and then develops as a distal and dying-back type of axonopathy.

Vitamin E-deficient animals show exudative diathesis, in which there is leakage of blood plasma from capillaries into subcutaneous tissues, apparently the result of abnormal permeability of capillary blood vessels. There is an accumulation of (usually green-colored) fluid under the skin. This responds to synthetic antioxidants or selenium.

There is also increased erythrocyte hemolysis, which responds to synthetic antioxidants or selenium. The sensitivity of erythrocytes to chemically induced hemolysis can be used both as a biological assay of vitamin E in experimental animals and also as an index of vitamin E nutritional status (Section 4.5).

Deficient animals may also show necrosis of the liver (which responds to selenium and synthetic antioxidants) and kidney (which responds to synthetic antioxidants but not selenium).

Most of these effects of vitamin E deficiency can be attributed to membrane damage. In deficiency, there is an accumulation of lysophosphatidylcholine in membranes, which is cytolytic. The accumulation of lysophosphatidylcholine is a result of increased activity of phospholipase A. It is not clear whether a-tocopherol inhibits phospholipase A; whether there is increased phospholipase activity because of increased peroxidation of polyunsaturated fatty acids in phospholipids, and hence an attempt at membrane lipid repair; or whether the physicochemical effects of a-tocopherol on membrane organization and fluidity prevent the cytolytic actions of lysophosphatidylcholine (Douglas et al., 1986; Erin et al., 1986).

Lipid peroxidation is increased in vitamin E deficiency, and subsequent catabolism of the peroxides results in the formation of malondialdehyde and other aldehydes. These can form Schiff bases with amino groups of proteins, free amino acids, and nucleic acids. The resultant fluorescent pigments are called ceroid pigments, lipopigments, or lipofuscin, and accumulate in increased amounts in the liver and other tissues of deficient animals (Manwaring and Csallany, 1988).

The formation of the ceroid pigments seems to represent a mechanism for detoxication of the products of lipid peroxidation and, although a useful indicator of peroxidation, and hence of vitamin E deficiency, seems to have no adverse effects under most conditions. The exception is in neuronal ceroid lipofuschinosis, which can result in physiological disturbance and nerve loss. Malondialdehyde attack on nucleic acids may be a factor in the induction of carcinogenesis in response to some oxidative radical-generating carcinogens. The formation of ceroid pigments can be prevented by synthetic antioxidants and possibly also selenium.

Vitamin E deficiency is also associated with impaired mitochondrial oxidative metabolism and impaired activity of microsomal cytochrome P450-dependent mixed-function oxidases, and hence the metabolism of xenobi-otics. There is no evidence that vitamin E has any specific role in electron transport in mitochondria or microsomes. Again, changes in membrane lipids and oxidative damage presumably account for the observed metabolic abnormalities.

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