VITAMIN A, CAROTENOIDS AND CELL FUNCTION.

Abstract

SummaryI. Both deficiency and excess of vitamin A produce many diverse pathological changes. Lipoprotein membranes have recently been found to be concerned in a number of the actions of excess of the vitamin. This article is devoted principally to a discussion of the interactions and possible functions of vitamin A within membranes, both in hypervitaminosis and under physiological conditions.2. Excess of vitamin A. (a) As a result of its amphipathic molecular structure, retinol is highly surface active. (b) The initial action of excess of retinol on erythrocytes is an expansion of the cell membrane; this is followed by haemolysis unless the cells are kept cold, or inhibitors, such as vitamin E, are present. (c) Addition of retinol to fibroblasts growing in vitro causes degranulation and swelling of the endoplasmic reticulum, swelling of Golgi vacuoles and mitochondria, and the formation of cytolysomes. (d) Isolated mitochondria from certain tissues also swell in the presence of retinol. This swelling is apparently not dependent on respiration, but is inhibited by vitamin E. (e) Lysosomal enzymes are released by excess of retinol, both in vivo and in vitro. A number of the effects of excess vitamin A on connective tissues may be ascribed to this action; these effects are inhibited by hydrocortisone, which stabilizes lysosomes, but are not significantly inhibited by vitamin E. (f) Closely related, but physiologically inactive, derivatives of retinol are relatively inactive towards membranes; membranes might therefore also be concerned in the physiological functions of retinol. (g) Vitamin A has recently been shown to have marked effects on the membranes of certain bacteria and viruses.3. Deficiency of vitamin A. (a) The diminished synthesis of mucopolysaccharide observed in deficiency may result from an interference with the synthesis of ‘active sulphate’ but, in view of conflicting observations, this cannot be considered as proven. (b) Suggestions have been made that lipoprotein membranes may be concerned in the actions of vitamin A on both mucopolysaccharide and steroid biosynthesis. (c) The action of the vitamin in biological oxidations is far from clear. Recently it has been found that deficiency increases, and excess of vitamin A decreases, the oxidation of succinate by homogenates of rat liver. (d) Organ culture experiments indicate that vitamin A acts directly on mouse prostate glands to prevent the squamous changes that are characteristic of deficiency.4. A conjugated chain of alternating single and double bonds is a chemical feature common to vitamin A and the carotenoids. (a) Such a chain is characterized by a high electron mobility; this has been studied both theoretically and experimentally in relation to electron transfer in photosynthesis, to ion transport, and to super‐conduction and semi‐conduction in biological systems. (b) The role of vitamin A in vision may be an evolutionary development of the function of the carotenoids in photosynthesis. In the eye, retinal is intimately concerned with the structure and function of lipoprotein membranes. We have suggested that changes in electron mobility may be functionally associated with the isomerization of 11‐CM retinal by light. (c) Vitamin A, or carotenoids, may be concerned in the receptor systems of olfaction and taste. (d) Photosynthesis in chloroplasts has many structural, chemical and functional features in common with respiration in mitochondria. Carotenoids are found in ox‐heart mitochondria but the presence of vitamin A is uncertain. (e) We have suggested that vitamin A or a metabolite retaining the conjugated chain may be present under physiological conditions in the lipids of biological membranes and that, by virtue of its mobile electrons, it may function in mitochondrial electron transport.5. Active forms of vitamin A.(a) Recent work indicates that retinoic acid, or a metabolite of retinoic acid, may be the active form. It has not been established conclusively, however, that retinoic acid is normally formed in vivo from retinol. (b) It is conceivable that, if vitamin A is concerned in electron transfer, the vitamin may penetrate lipoprotein membranes as retinol and that it may subsequently be converted to a functional derivative. In this way, the membranes of animal cells may receive the carotenoid skeleton which, unlike plant and bacterial cells, they cannot synthesize for themselves.We are most grateful to Dame Honor Fell, F.R.S., Sir Rudolph Peters, F.R.S., and Miss Audrey M. Glauert for reading the manuscript of this article and for their helpful suggestions. We thank Mr R. A. Parker and Mr I. Armond for preparing the plates and figures, and Mrs M. Wright for her careful typing.