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Metabolic functions of vitamin A

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1 Metabolic functions of vitamin A
Domina Petric, MD

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

3 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. Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

4 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). Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

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

6 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. Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

7 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. Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

8 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. Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

9 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. Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

10 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. Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

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

12 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. Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

13 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 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

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

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

16 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. Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

17 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) Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

18 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. Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

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

20 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. Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

21 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. Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

22 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. Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

23 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. Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

24 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. Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

25 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. Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

26 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. Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

27 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. Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

28 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. Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

29 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. Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

30 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. Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

31 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 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

32 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. Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

33 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. Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

34 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. Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

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

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

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