Retinoids Carotenoids Have Vitamin A Activity Figure 451

Retinoids comprise retinol, retinaldehyde, and retinoic acid (preformed vitamin A, found only in foods of animal origin); carotenoids, found in plants, comprise carotenes and related compounds, known as provitamin A, as they can be cleaved to yield retinaldehyde and thence retinol and retinoic acid. The a-, ß-, and Y-carotenes and cryptoxanthin are quantitatively the most important provitamin A carotenoids. Although it would appear that one molecule of ß-carotene should yield two of retinol, this is not so in practice; 6 |g of ß-carotene is equivalent to 1 |g of preformed retinol. The total amount of vitamin A in foods is therefore expressed as micrograms of retinol equivalents. Beta-carotene and other provitamin A carotenoids are cleaved in the intestinal mucosa by carotene dioxygenase, yielding retinaldehyde, which is reduced to retinol, esterified, and secreted in chylomi-

Figure 45-1. p-Carotene and the major vitamin A vitamers. * Shows the site of cleavage of p-carotene into two molecules of retinaldehyde by carotene dioxygenase.

H3C CH

H3C CH

H3C CH3 CH3

h3c ch3 c^3

H3C CH3 1 3

All-f/ans-retinoic acid

H3C CH3

p-Carotene

CH2OH Retinol

COOH

H3C CH3 CH3

CHO Retinaldehyde

H3C CH3 3

H3C CH3 3

COOH 9-c/s-retinoic acid

COOH 9-c/s-retinoic acid crons together with esters formed from dietary retinol. The intestinal activity of carotene dioxygenase is low, so that a relatively large proportion of ingested P-carotene may appear in the circulation unchanged. While the principal site of carotene dioxygenase attack is the central bond of P-carotene, asymmetric cleavage may also occur, leading to the formation of 8'-, 10'-, and 12'-apo-carotenals, which are oxidized to retinoic acid but cannot be used as sources of retinol or retinaldehyde.

Vitamin A Has a Function in Vision

In the retina, retinaldehyde functions as the prosthetic group of the light-sensitive opsin proteins, forming rhodopsin (in rods) and iodopsin (in cones). Any one cone cell contains only one type of opsin and is sensitive to only one color. In the pigment epithelium of the retina, all-trans-retinol is isomerized to 11-cis-retinol and oxidized to 11-cis-retinaldehyde. This reacts with a lysine residue in opsin, forming the holoprotein rhodopsin. As shown in Figure 45-2, the absorption of light by rhodopsin causes isomerization of the retinaldehyde from 11-cis to all-trans, and a conformational change in opsin. This results in the release of retinaldehyde from the protein and the initiation of a nerve impulse. The formation of the initial excited form of rhodopsin, bathorhodopsin, occurs within picoseconds of illumination. There is then a series of conformational changes leading to the formation of metarhodopsin II, which initiates a guanine nucleotide amplification cascade and then a nerve impulse. The final step is hydrolysis to release all-trans-retinaldehyde and opsin. The key to initiation of the visual cycle is the availability of 11-cis-retinaldehyde, and hence vitamin A. In defi ciency, both the time taken to adapt to darkness and the ability to see in poor light are impaired.

Retinoic Acid Has a Role in the Regulation of Gene Expression & Tissue Differentiation

A most important function of vitamin A is in the control of cell differentiation and turnover. All-trans-retinoic acid and 9-cis-retinoic acid (Figure 45-1) regulate growth, development, and tissue differentiation; they have different actions in different tissues. Like the steroid hormones and vitamin D, retinoic acid binds to nuclear receptors that bind to response elements of DNA and regulate the transcription of specific genes. There are two families of nuclear retinoid receptors: the retinoic acid receptors (RARs) bind all-trans-retinoic acid or 9-cis-retinoic acid, and the retinoid X receptors (RXRs) bind 9-cis-retinoic acid.

Vitamin A Deficiency Is a Major Public Health Problem Worldwide

Vitamin A deficiency is the most important preventable cause of blindness. The earliest sign of deficiency is a loss of sensitivity to green light, followed by impairment of adaptation to dim light, followed by night blindness. More prolonged deficiency leads to xerophthalmia: keratinization of the cornea and skin and blindness. Vitamin A also has an important role in differentiation of immune system cells, and mild deficiency leads to increased susceptibility to infectious diseases. Furthermore, the synthesis of retinol-binding protein in response to infection is reduced (it is a negative acute phase protein), decreasing the circulating vi-

h3c ch ch2oh

All-trans-retinol

11-c/s-Retinol

11-c/s-Retinaldehyde h3c ch ch2oh

All-trans-retinol

11-c/s-Retinol

11-c/s-Retinaldehyde

Lysine residue I in opsin NH

nCH3 Photorhodopsin

I 45 psec Bathorhodopsin

I 30 nsec ü Lumirhodopsin

0 I 75 ^sec j= Metarhodopsin I

1 1 10 msec GDP

Lysine residue I in opsin NH

nCH3 Photorhodopsin

I 45 psec Bathorhodopsin

I 30 nsec ü Lumirhodopsin

0 I 75 ^sec j= Metarhodopsin I

1 1 10 msec GDP

I minutes GTP Metarhodopsin III

cGMP

Na+channel open s Inactive

5'GMP

Na+channel closed

—*- Active * phosphodiesterase cGMP

Na+channel open s Inactive

Transducin-GTP

Transducin-GDP

Transducin-GDP

H3C CH3

XCH All-trans-retinaldehyde + opsin

Figure 45-2. The role of retinaldehyde in vision.

tamin, and therefore there is further impairment of immune responses.

Vitamin A Is Toxic in Excess

There is only a limited capacity to metabolize vitamin A, and excessive intakes lead to accumulation beyond the capacity of binding proteins, so that unbound vitamin A causes tissue damage. Symptoms of toxicity affect the central nervous system (headache, nausea, ataxia, and anorexia, all associated with increased cerebrospinal fluid pressure), the liver (hepatomegaly with histologic changes and hyperlipidemia), calcium homeostasis (thickening of the long bones, hypercalcemia and calcification of soft tissues), and the skin (excessive dryness, desquamation, and alopecia).

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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