Nongenomic Actions of Retinoids

In addition to its genomic functions, retinoic acid also has a number of non-genomic functions. It enhances the stability of keratin mRNA, leading to increased synthesis of this protein (Crowe, 1993). Retinoic acid acts also as an effector in response to transmembrane signaling by retinoylation of target proteins.

In the synthesis of most glycoproteins containing mannose, the intermediate carrier of the mannosyl moiety is the polyene dolichol phosphate. However, in some systems, retinyl phosphate can act as the intermediate carrier between UDP-mannose and the acceptor glycoprotein. Retinyl phosphate mannose seems to be involved especially in the synthesis of hydrophobic regions of glycoproteins (DeLuca, 1977; Frot-Coutaz etal., 1985).

2.3.3.1 Retinoylation of Proteins Studies with knockout mice, lacking nuclear retinoid receptors, suggest that retinoic acid has physiological functions unrelated to its genomic actions. Label from [3H]retinoic acid is incorporated into cells in culture in a form that is not extractable by organic solvents, suggesting that there is covalent binding of retinoic acid to proteins - retinoylation.

There are two main routes involved in the retinoylation of proteins:

1. Formation of retinoyl CoA, followed by formation of an ester with the hydroxyl group of tyrosine, threonine or serine, or a thio-ester with the sulfhydryl group of cysteine (Figure 2.7). The source of retinoic acid for

thio-ester to cysteine

thio-ester to cysteine amide to amino terminal amino acid j Figure 2.7. Retinoylation of proteins by retinoyl CoA.

amide to amino terminal amino acid j Figure 2.7. Retinoylation of proteins by retinoyl CoA.

this reaction may be retinoyl glucuronide (Section 2.2.1.3) rather than free retinoic acid.

2. Cytochrome P450-catalyzed 4-hydroxylation, followed by formation of an ether bond to the hydroxyl group of tyrosine, threonine or serine, or a thio-ether bond to the sulfhydryl group of cysteine (Figure 2.8).

Both in cells in culture and in vivo, the major targets for retinoylation are the regulatory subunits of cAMP-dependent protein kinases, suggesting a role for retinoic acid in modulation of the actions of cell surface acting hormones and neurotransmitters (Myhre et al., 1996). In a variety of cell types, cAMP-dependent protein kinase activity increases after exposure to retinoic acid. In a number of experimental situations, retinoic acid and cAMP act synergistically in cell differentiation. Takahashi et al. (1997) reported that 40 different proteins

ether bond to serine, threonine or tyrosine thio-etber bond to cysteine

Figure 2.8. Retinoylation of proteins by 4-hydroxyretinoic acid.

ether bond to serine, threonine or tyrosine thio-etber bond to cysteine

Figure 2.8. Retinoylation of proteins by 4-hydroxyretinoic acid.

are retinoylated in cells in culture, whereas cells in which the ras oncogene has been activated and that are insensitive to growth inhibition by retinoic acid, only 15 proteins are retinoylated (Takahashi et al., 1997).

2.3.3.2 Retinoids in Transmembrane Signaling Neutrophils treated with physiological concentrations of all-frans-retinoic acid show a dose-dependent increase in synthesis of superoxide. Inhibitor studies suggest that retinoic acid acts via an inositol trisphosphate cascade rather than calcium and protein kinase C (Koga et al., 1997). There is also evidence that all-frans-retinoic acid leads to increased formation of cADP-ribose and nicotinic acid adenine din-ucleotide phosphate as second messengers (Section 8.4.4; Dousa et al., 1996; Mehta and Cheema, 1999).

Some of the retroretinoids also have cell signaling functions at a cell surface or a cytoplasmic receptor. 14-Hydroxyretroretinol is required for lymphocyte proliferation, whereas anhydroretinol is a growth inhibitor; the two compounds act antagonistically. Treatment of T lymphocytes with an-hydroretinol in the absence of 14-hydroxyretroretinol leads to rapid cell death, with widespread morphological changes but little or no nuclear abnormality. This suggests a cytoplasmic mechanism of apoptosis (O'Connell et al., 1996).

There is also evidence that retinoic acid directly modulates transmission at electrical synapses of retinal cells. This is independent of G-proteins and second messengers, and involves a nonnuclear RAR-like binding site associated with ion channels (Zhang and McMahon, 2000).

2.4 VITAMIN A DEFICIENCY (XEROPHTHALMIA)

Vitamin A-deficient experimental animals fail to grow; adults are blind and sterile, with testicular degeneration in males and keratinization of the uterine epithelium in females. Although deficient female animals will conceive, and the fetuses will implant, formation of the placenta is impaired and the fetuses are resorbed. Epithelia in general are hyperplastic and keratinized, and there is impaired cellular immunity with increased susceptibility to infection. Both retinol and retinoic acid are required for gestation in the rat; in deficient animals, retinoic acid alone will not prevent fetal resorption after about day 10 of gestation (Wellik and DeLuca, 1995; Wellik et al., 1997).

Vitamin A deficiency is a major problem of children under five in developing countries, being the single most common preventable cause of blindness. Table 2.1 shows the prevalence of vitamin A deficiency in different regions of the world. The increased susceptibility to infection and impairment of immune responses in vitamin A deficiency causes significant childhood mortality. A number of trials of vitamin A supplementation in areas of endemic deficiency show a 20% to 35% reduction in child mortality.

Table 2.1 Prevalence of Vitamin A Deficiency among Children under Five

Subclinical Deficiency

Clinical Deficiency

WHO Region

Millions

% Prevalance

Millions

% Prevalance

Africa

49

45.8

1.08

1.0

Americas

17

21.5

0.06

0.1

Southeast Asia

125

70.2

1.3

0.7

Europe

Eastern Mediterranean

23

31.5

0.16

0.3

Western Pacific

42

30.0

0.1

0.1

Total

256

40.3

2.7

0.1

WHO, World Health Organization.

WHO, World Health Organization.

Functional vitamin A deficiency may occur despite adequate liver reserves of retinol, as a result of impaired synthesis of RBP in protein-energy malnutrition, and possibly also in zinc deficiency (Smith et al., 1973; Solomons and Russell, 1980; Rahman et al., 2002).

A mild infection, such as measles, commonly triggers the development of xerophthalmia in children whose vitamin A status is marginal. In addition to functional deficiency as a result of impaired synthesis of RBP (Section 2.2.3) and transthyretin in response to infection, there may be a considerable urinary loss of vitamin A because of increased renal epithelial permeability and proteinuria, permitting loss of retinol bound to RBP-transthyretin. The American Academy of Pediatrics Committee on Infectious Diseases (1993) recommended vitamin A supplements for all children who have been hospitalized with measles.

In adults, excessive alcohol consumption reduces liver reserves of vitamin A, both as a result of alcoholic liver damage and also by induction of cytochrome P450 enzymes that catalyze the oxidation of retinol to retinoic acid (as also occurs with chronic use of barbiturates). However, chronic consumption of alcohol can also potentiate the toxicity of retinol (Section 2.5.1).

Even marginal vitamin A status leads to significantly impaired resistance to infection, and deficient children are significantly more prone to infection. A number of studies show beneficial effects of vitamin A supplementation, and adverse effects of marginal status in measles, diarrheal and respiratory diseases, malaria, human immunodeficiency virus (HIV) infection, and tuberculosis (Semba, 1999; Semba and Tang, 1999). The vitamin has multiple effects on the immune system, including modulating the expression of cytokines, and the differentiation, function, and apoptosis of macrophages, T and B lymphocytes, neutrophils, and other cells.

Mild deficiency results in impaired dark adaptation; as the deficiency progresses, there is inability to see in the dark (night blindness). As discussed in Section 2.3.1, the recycling of retinaldehyde to reform rhodopsin is the rate-limiting step in the visual cycle. If reserves of retinaldehyde in the pigment epithelium are inadequate, then there will be slow dark adaptation and impaired vision in poor light. More prolonged and severe deficiency leads to conjunctival xerosis - squamous metaplasia and keratinization of the epithelial cells of the conjunctiva with loss of goblet cells in the conjunctival mucosa, leading to dryness, wrinkling, and thickening of the cornea (xerophthalmia). As the deficiency progresses, there is keratinization of the cornea. At this stage, the condition is still reversible, although there may be residual scarring of the

Table 2.2 WHO Classification of Xerophthalmia Classification Code Clinical Description

Prevalence among Preschool Children to Indicate Significant Public Health Problems

XN

Night blindness

>1%

X1A

Conjunctival xerosis

X1B

Bitot's spots

>0.5%

X2

Corneal xerosis

X3A

Corneal ulceration/keratomalacia

>0.01%

involving less than one-third of

the corneal surface

X3B

Corneal ulceration/keratomalacia

>0.01%

involving more than one-third

of the corneal surface

XS

Corneal scar

>0.05%

XF

Xerophthalmic fundus

Biochemical

Plasma retinol <0.35 |xmol/L

>5%

cornea. In advanced xerosis, yellow-gray foamy patches of keratinized cells and bacteria (Bitot's spots) may accumulate on the surface of the conjunctiva. The next stage is ulceration of the cornea from increased proteolytic action, thus causing irreversible blindness (Pirie et al., 1975). Table 2.2 shows the World Health Organization classification of xerophthalmia.

As well as the conjunctiva, other epithelia are affected by moderate or mild vitamin A deficiency, with increased intestinal permeability to disaccharides, later a reduction in the number of goblet cells per villus, and then a reduction in mucus secretion (McCullough et al., 1999). There is also atrophy of the respiratory epithelium, again with loss of goblet cells, followed by keratinization, resulting in increased susceptibility to infection. These changes in intestinal and respiratory epithelium develop earlier than the more readily observed diagnostic changes in the eye.

In adults maintained on vitamin A-deficient diets for a period of months, there are a number of early signs, apparent before the impairment of dark adaptation: impairment of the senses of taste, smell, and balance and distortion of color vision, with impaired sensitivity to green light. With the exception of the effects on color vision, these can all be attributed to dedifferentiation of ciliated epithelia (Sauberlich et al., 1974; Hodges et al., 1978).

Early studies showed impaired gluconeogenesis and low hepatic stores of glycogen in vitamin A-deficient animals. Synthesis of one of the key regulatory enzymes of glycolysis, the GTP-dependent isoenzyme of phosphoenolpyru-vate carboxykinase, is regulated by all-frans-retinoic acid. Both gene expression and gluconeogenesis fall in vitamin A deficiency (Shin and McGrane, 1997).

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