Carotenoid Oxygenase

Vitamin A Metabolism

Vitamin A has three active forms (retinal, retinol and retinoic acid) and a storage form (retinyl ester):

Retinyl ester ß à Retinol ß à Retinal à Retinoic acid

Circulating retinol is primarily bound to retinol-binding protein (RBP), and can enter and leave the liver several times per day in a process known as retinol recycling, which acts to relate the amount of retinol in circulation and protects cells from the damaging effects of free retinol or retinoic acid. Retinol bound to a cellular RBP (CRBP or CRBP-II) can be esterified by the enzyme lecithin:retinol acyltransferase (LCAT), the resulting retinyl ester being stored primarily in liver stellate cells. LCAT provides a readily retrievable storage form of vitamin A, as well as regulating its availability for other pathways.

Vitamin A is required throughout life and participates in numerous cellular activities involved in reproduction, embryonic development, vision, growth, cellular differentiation and proliferation, tissue maintenance and lipid metabolism. The three active forms of vitamin A each serve different overlapping functions. For instance, retinal is required for rhodopsin formation and vision, while retinoic acid is the principal hormonal metabolite required for proper growth and differentiation of epithelial cells. Some of the major roles of vitamin A are discussed below:

Vision and Vitamin A

Vitamin A is required for the formation of the photoreceptor rhodopsin, which is a complex of retinal and the vision protein opsin, where retinal functions as the chromophore. Rhodopsins are found in animals and green algae where they act as regulators of light-activated photochannels, and in archaea where they act as light-driven ion pumps. In animals, the light-sensitive pigment rhodopsin occurs embedded in the membrane of rod cells in the retina at the back of the eye. When light passes through the lens, it is sensed in the retina by both rod cells (black and white vision) and cone cells (colour vision). In rod cells, the exposure of rhodopsin to light causes 11-cis-retinal to be released from opsin, resulting in a conformational change in the photoreceptor that activates the G-protein transducin. Transducin activation leads to the closure of the sodium channel in the membrane and the hyperpolarisation of the rod cell, which propagates a nerve impulse to the brain that is perceived as light. Rod cells are especially important for night vision as they can detect very small amounts of light. Inadequate amounts of retinol can led to Night Blindness and corneal malformations, therefore eating carrots does let you see better in the dark!

Gene Expression and Vitamin A

Retinol and retinoic acid are important signalling molecules in vertebrates that act to alter the transcriptional activation or repression of numerous genes. Several of these retinoid-controlled genes are involved in growth and differentiation, such as those involved in the differentiation of the three germ layers, organogenesis and limb development during embryogenesis. Retinoic acid exerts its effect through its binding to retinoic acid receptors (members of the steroid hormone superfamily of proteins), where the vitamin-receptor complex interacts with the genes. Two families of receptors interact with vitamin A: the retinoic acid receptor (RAR) family that bind all-trans-retinoic acid (and 9-cis-retinoic acid), and the retinoic acid X receptor (RXR) family that bind only 9-cis retinoic acid. Together these receptors can regulate the rate of gene expression. Both vitamin A deficiency and excess can cause birth defects.

Immunity and Vitamin A

Vitamin A is required for the normal functioning of the immune system. Retinol and its derivatives are required for the maintenance of the skin and mucosal cells that function as a barrier against infection, and are also required for the development of white blood cells that play a critical role in mounding an immune response. For example, the activation of T-cell lymphocytes requires the binding of the RAR receptor to retinoic acid. A deficiency in vitamin A can cause the mucosal membranes to atrophy, decreasing resistance to infection, and can increase the severity of infection. As such, vitamin A deficiency can be regarded as a nutritionally acquired immunodeficiency disease.

Cancer and Vitamin A

Vitamin A intake has a complex relationship with cancer prevention: while small doses of vitamin A or beta-carotene appear to help prevent cancer, higher doses seem to have the reverse effect. The anti-cancer effects of beta-carotene appear to stem from its anti-oxidative ability to scavenge for reactive oxygen species, as well as through its conversion to vitamin A, which can improve immune function in addition to eliciting an anti-proliferative effect through the RAR and RXR receptors, thereby acting to block certain carcinogenic processes and inhibit tumour cell growth. However, an excessive intake of beta-carotene appears to have carcinogen effects, possibly through its promotion of the eccentric (or asymmetric) pathway of beta-carotene cleavage, which produces breakdown products that might lead to the destruction of retinoic acid through the activation of the P450 enzyme, which in turn could decrease retinoid signalling leading to enhanced cell proliferation. Therefore dosage seems to be an important factor in beta-carotene action.

Red Blood Cell Development and Vitamin A

Vitamin A is also involved in the production of red blood cells, which are derived from stem cells that are dependent upon retinoids for their proper differentiation. In addition, vitamin A appears to facilitate the mobilisation of iron stores to developing red blood cells, where it is incorporated into the oxygen carrier haemoglobin.