Metabolic functions of vitamin A Domina Petric, MD

Vitamin A in vision I. 18.9.2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Vitamin A in vision Vitamin A in the visual process, as 11-cis-retinal, serves as the photosensitive chromophoric group of the visual pigments of rod and cone cells of the retina. 18.9.2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Vitamin A in vision Rod cells contain the pigment rhodopsin. Cone cells contain one of three possible iodopsins. In each case, 11-cis retinal is bound (via formation of a Schiff base) to a specific lysyl residue of the apo-protein (collectively referred to as opsins). 18.9.2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Vitamin A in vision Photoreception is effected by the rapid, light-induced isomerization of 11-cis retinal to the all-trans form. 18.9.2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Bleaching The dissociation of all-trans-retinal and opsin is coupled to nervous stimulation of the vision centers of the brain. The bleaching of rhodopsin causes the closing of Na+ channels in the rod outer segment, thus leading to hyperpolarization of the membrane. 18.9.2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Bleaching Change in membrane potential is transmitted as a nervous impulse along the optic neurons. This response is stimulated by the reaction of an unstable “activated” form of rhodopsin, metarhodopsin II, which reacts with transducin, a membrane-bound G protein of the rod outer segment disks. The result is the binding of the transducin α subunit with cGMP phosphodiesterase, which activates the latter to catalyze the hydrolysis of cGMP to GMP. 18.9.2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Bleaching Because cGMP maintains Na+ channels of the rod plasma membrane in the open state, the resulting decrease in its concentration causes a marked reduction in Na+ influx. This results in hyperpolarization of the membrane and the generation of a nerve impulse through the synaptic terminal of the rod cell. 18.9.2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Visual process It is cyclic process. All-trans-retinal can be converted enzymatically in the dark back to the 11-cis form. After bleaching, all-trans-retinal is rapidly reduced to all-trans-retinol, in the rod outer segment. All-trans-retinol is then transferred into the retinal pigment epithelial cells, where it is esterified (with palmitic acid) and stored in the bulk lipid of those cells. 18.9.2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Cones Cones have much lower (100-fold) light sensitivity but faster (10-fold) recovery rates than rods. In cones the oxidation of 11-cis-retinol to 11-cis-retinal is NADP-dependent. The isomerization of all trans to 11-cis-retinal occurs in a two-step process in Müller cells. 18.9.2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Rods In rods, the oxidation step is NAD-dependent. The isomerization is a one step process in the retinal pigment epithelium. 18.9.2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Melanopsin The photosensitive pigment melanopsin undergoes light-induced isomerization of 11-cis-retinal to 11-trans-retinal. Unlike rhodopsin, it does not dissociate from the prosthetic group. Melanopsin is found in the inner retina (not in rods or cones) and in the site of the circadian clock of the brain. Melanopsin function is photoperiod regulation. 18.9.2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Optimal light conditions Dim light (night vision) Rod cells Cone cells Location in retina Around periphery Around centre Optimal light conditions Dim light (night vision) Bright light (day vision) Visual acuity Low resolution (many rods: one bipolar cell) High resolution (one cone: one bipolar cell) Colour sensitivity All wavelenghts Certain wavelenghts (red, green, blue) Type of vision Achromatic (black or white) Colour Number of types One (all contain rhodopsin) Three different iodopsin pigments Relative abundance Many Fewer 18.9.2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

night blindness or nyctalopia. Deprivation of vitamin A disrupts the visual cycle, resulting in impaired dark adaptation: night blindness or nyctalopia. 18.9.2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Systemic functions of vitamin A II. 18.9.2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Vitamin A regulation of gene transcription Vitamin A discharges its systemic functions through the abilities of all-trans-retinoic acid and 9-cis-retinoic acid to regulate gene expression at specific target sites in the body. Retinoid regulation of transcription is receptor mediated. 18.9.2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Vitamin A regulation of gene transcription Retinoic acid binds to two members of a highly conserved superfamily of proteins that act as nuclear receptors for steroid hormones: 1,25-(OH)2-vitamin D3 thyroid hormone (T3) 18.9.2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Role of vitamin A in embryonic development Vitamin A is essential for growth, fetal development, and tissue maintenance. The major organs affected in vitamin A deficiency are the heart and tissues of the ocular, circulatory, urogenital, and respiratory systems. 18.9.2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Role of vitamin A in reproduction Vitamin A is necessary for reproduction. 18.9.2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Role of vitamin A in bone metabolism Vitamin A has an essential role in the normal metabolism of bone. Both low and high vitamin A intakes lead to impaired bone mineral density. In humans, bone mineral density is optimized with intakes of 0.6–0.9 mg RE/day. 18.9.2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Role of vitamin A in hematopoesis Chronic deprivation of vitamin A leads to anemia. Supplemental vitamin A has been shown to increase iron status in anemic, vitamin A-deficient patients. Retinoids are involved in the differentiation of myeloid cells into neutrophils, which occurs in the bone marrow. 18.9.2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Role of vitamin A in immunity Vitamin A-deficient patients are typically more susceptible to infection than are individuals of adequate vitamin A nutriture. Alterations caused by vitamin A deficiency provide environments conducive to bacterial growth and secondary infection in loci obstructed by keratinizing debris. 18.9.2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Role of vitamin A in immunity Vitamin A deficiency induces inflammation and exacerbates inflammatory states. Retinol may be a specific growth factor for B lymphocytes. Lower antibody titers have been reported for vitamin A-deficient children. 18.9.2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Role of vitamin A in immunity Vitamin A deficiency impairs innate and adaptive immunity. It has been suggested that the deficiency may increase the risk of HIV transmission. 18.9.2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Retinoids vs. carotenoids Retinoids seem to act on the differentiation of immune cells, increasing mitogenesis of lymphocytes and phagocytosis of monocytes and macrophages. Carotenoids seem to affect immunosurveillance of activated NK cells and helper T cells by modifying the release of at least some cytokine-like products by activated lymphocytes and monocytes. 18.9.2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Role of vitamin A in immunity Active infection appears to alter the utilization or, at least, the distribution of vitamin A among tissues. Plasma retinol concentrations drop during malarial attacks, chickenpox, diarrhea, measles, and respiratory disease. 18.9.2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Role of vitamin A in immunity Episodes of acute infection have been found to be associated with eightfold increases in the urinary excretion of retinol and RBP. 18.9.2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Role of vitamin A in immunity Vitamin A deficiency is typically associated with malnutrition, particularly protein-energy malnutrition. Protein deficiency also impairs the synthesis of apo-RBP, CRBP, and other retinol binding proteins, impairing vitamin A transport and cellular utilization. Vitamin A deficiency is known to induce or exacerbate inflammation. 18.9.2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Role of vitamin A in immunity Epidemiologic studies have found that low vitamin A status is frequently associated with increased disease incidence and mortality rates. 18.9.2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Vitamin A and skin Vitamin A appears to have a role in the normal health of the skin. Its vitamers, as well as carotenoids, are typically found in greater concentrations in the subcutis than in the plasma. Vitamin A deficiency impairs the terminal differentiation of human keratinocytes and causes the skin to be thick, dry, and scaly. It also results in obstruction and enlargement of the hair follicles. 18.9.2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Clinical applications of retinoids in the treatment of dermatologic diseases Precancerous lesions: actinic keratoses Skin cancer: nonmelanoma (squamous and basal) skin cancer Photo-aging: sun damage (roughness, drying, wrinkling, mottled pigmentation, laxity) Acne vulgaris: comedonal and cystic acne Psoriasis and keratinization disorders: erythrodermic, pustular, and calcitrant psoriasis 18.9.2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Role of vitamin A in drug metabolism Vitamin A deficiency can reduce hepatic cytochrome P-450 contents and related enzyme activities. Vitamin A supplementation has been shown to increase the activities of cytochrome P-450 isozymes. 18.9.2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Antioxidant activities of vitamin A and carotenoids Several carotenoids have been shown to have direct antioxidant activities: β-carotene, lycopene and some oxycarotenoids (zeaxanthin, lutein). Carotenoids can also participate in the reduction of free radicals: xanthophyll carotenoids (lutein, lycopene and β-crypto xanthin) are more effective than β-carotene. 18.9.2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Role of vitamin A in reducing heart disease risk Plasma retinol levels have been found to be related inversely to the risk of ischemic stroke. Low plasma β-carotene concentrations are associated with increased risk of myocardial infarction. 18.9.2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Role of vitamin A in carcinogenesis Squamous metaplastic changes Leukoplakia Conversion of papillomas to carcinomas 18.9.2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Literature Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008. 18.9.2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.