General Aspects Of Retinol Transport And Metabolism In Mammalian Species

The retinol (vitamin A) belongs to the "retinoids" family including both the compounds possessing one of the biological activities of the retinol (ROH) and the many synthetic analogues related structurally to the retinol, with or without a biological activity. Provitamin A is the dietary source of retinol and is supplied as carotenoids (mainly b-carotene) in vegetables and preformed retinyl esters (long-chain fatty acid esters of retinol: palmitate, oleate, stearate, and linoleate) in animal meat (Blomhoff, 1994). Retinol plays a central role in many essential biological processes such as vision, immunity, reproduction, growth, development, control of cellular proliferation, and differentiation (Chambon, 1996). The main active forms of retinol are retinoic acids (RAs), except for reproduction and vision, where retinol and retinal also play important roles.

Two vehicles are described for mammalian blood transport of retinoids. First, the retinyl esters and carotenoids can be incorporated in intact or remnant chylomicrons or very low-density lipoproteins (Debier and Larondelle, 2005). Second, the main form of retinol blood transport (1 mmol/l) is the association with a specific binding protein (RBP), which is itself

'Abbreviations: ADH, alcohol dehydrogenases; CRABP, cellular retinoic acid-binding protein; CRBP, cellular retinol-binding protein; dpc, days post coitum; LRAT, lecithin retinol acyltransferase; RA, retinoic acid; Ral, retinaldehyde; RALDH, retinaldehyde dehydrogenase; RBP, retinol-binding protein; RDH, retinol dehydrogenase; ROH, retinol.

complexed with transthyretin (ratio 1 mol/1mol). The constitution of this ternary complex prevents the glomerular filtration of the small RBP-retinol form (21 kDa) and increases the affinity of RBP for retinol (Bellovino et al., 2003). A binding to other plasma proteins, such as albumin or lipocalins, is also described for retinol. Albumin could serve as a transporter for RA, which circulates in very small levels in the blood. The transfer of retinol to target cells involves a specific membrane-bound RBP receptor (Sivaprasadarao et al., 1998). To date, the debate still remains concerning the molecular mechanisms of the cellular retinol penetration: endocytosis, dissociation of RBP-retinol complex, and intracellular degradation of RBP or extracellular dissociation of RBP-retinol complex and delivery of retinol via transmembrane pore. The uptake of remnant chylomicrons and very low-density lipoproteins (containing retinyl esters and carotenoids) is realized by target tissues using, respectively, the lipoprotein lipase and low-density lipoproteins receptor pathways. Bound to albumin, RA can be transferred into the tissues by passive diffusion, with an efficiency of transfer, which is cell type and tissue specific.

To be biologically active (Fig. 1), retinol must first be oxidized to retinaldehyde and then to RA. A large number of enzymes catalyze the reversible oxidation of retinol to retinaldehyde: the alcohol dehydrogenases (ADH), the retinol dehydrogenase (RDH) of the microsomal fraction, and some members of the cytochrome P450 family. Several enzymes are able to catalyze irreversibly the oxidation of retinaldehyde to RA: the retinal dehydrogenases (RALDH1, 2, 3, and 4) and also members of the cytochrome P450 family (Liden and Eriksson, 2006). These enzymatic reactions could be antagonized and/or stopped by several toxic molecules, namely ethanol, citral, nitrofen, or bisdiamine, leading to an exogenous alteration of RA production. Specific isomerization reactions are also likely to occur within the cells, since there are at least two RA stereoisomers in vivo (all-trans and 9-cis RA) exhibiting distinct biochemical activities. The catabolism of all-trans and 9-cis RA is also an important mechanism for controlling RA levels in cell and tissues and is carried out by three specific members of cytochrome P450s, CYP26A1, B1, and C1 (19). RA is catabolized to products such as 4-oxo-RA, 4-hydroxy-RA, 18-hydroxy-RA, and 5,18-epoxy-RA, which are finally excreted. These compounds can also undergo glucuronidation (Marill et al., 2003). An alternative metabolic pathway was present for intracellular retinol: the formation and storage as retinyl esters. Indeed, retinol may be esterified by two enzymes (lecithin retinol acyltransferase and diacylglycerol O-acyltransferase) into mostly long-chain retinyl esters such as retinyl palmitate, stearate, oleate, and linoleate. These esters are then stored in cytosolic lipid droplets. The mobilization of these retinyl esters and the release of retinol esters are realized by a retinyl ester hydrolase.

Since retinol, retinaldehyde, and RA are lipids, they lack appreciable water solubility and consequently must be bound to proteins within cells. Several intracellular-binding proteins for retinol, retinaldehyde, and RA

^-Carotene

,' Nuclear membrane

CH3. CH3CH3 CH3 C

CRBPs

Retinol

Lipid

ADHs

SDRs

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