Retinal reductase

Carotenoids, also in micellular form, are absorbed into the duodenal mucosal cells by passive diffusion. The efficiency of absorption of carotenoids is much lower than for vitamin A, between 9% and 22%, and is subject to a large number of variables, including carotenoid type, the amount in the meal, matrix properties, nutrient status, and genetic factors. Once inside the mucosal cell, (3-carotene is principally converted to retinal by the enzyme p-carotene-15,15 -dioxygenase, the retinal being converted by retinal reductase to retindl and esterified, though it can also be cleaved eccen-... 

Retinaldehyde, when bound to retinol binding protein II (CRBPII), serves as a substrate for retinal reductase resulting in the production of retinol (14), which then binds to cellular retinol binding protein (CRBP) forming holo-CRBP. Holo-CRBP seems to be the preferred substrate for an esterification reaction (Fig. 7.6) mediated by lecithin retinol acyl transferase (LRAT), a microsomal enzyme that uses acyl groups donated from phosphatidylcholine (14).In cells not expressing CRBP, retinol esterification is carried out by a different enzyme, acyl CoArretinol acyl transferase (ARAT). 

CRBP(II) sequesters atRCHO generated from carotenoids and allows its reduction into atROH, catalyzed by an ER retinal reductase (uncharacterized). In contrast to CRBP(I), CRBP(II) does not allow oxidation/dehydrogenation of its ligands. LRAT accesses the CRBP(II)-atROH complex and produces atRE for incorporation into chylomicrons. During conversion into remnants by lipoprotein lipase in adipose, chylomicrons retain most of their RE, as they do cholesterol esters. 

Aukunuru, JV, Sunkara, G, Bandi, N, Thoreson, WB, and Kompella, UB, 2001. Expression of multidrug resistance-associated protein (MRP) in human retinal pigment epithelial cells and its interaction with BAPSG, a novel aldose reductase inhibitor. Pharm Res 18, 565-572. 

The standard assay contained retinal homogenate (0.2-3 mg protein), 0.05 mAf tyrosine, 1 mAf (6i ,S)-5,6,7,8-tetrahydro-L-biopterin, 3.5 mAf NADH, 0.02 unit of dihydroxypteridine reductase, 15 ng catalase, 40 mAf sodium acetate buffer (pH 6.0), and 0.1 mAf o-benzylhydroxylamine (inhibitor of Dopa decarboxylase) in a final volume of 100 fiL. After incubation of the mixture at 37°C for 5 to 20 minutes, the reaction as stopped by adding 100 fiL of 0.5 Af perchloric acid containing 0.4 mAf sodium metabisulfite and 0.1 mAf disodium EDTA. The supernate obtained after centrifugation was used for HPLC analysis. 

Retinal is reduced to retinol by retinaldehyde reductase, an NADPH requiring enzyme within the intestines. 

Loss of mural cells (pericytes) in the retinal microcapillaries is a typical event in diabetic retinopathy. These mural cells contain aldose reductase and accumulate sorbitol in experimental hyperglycaemia (Buzney et al., 1977), leading to degenerative changes implying participation of the polyol pathway in cell death. 

Use of aldose reductase inhibitors prevents the loss of pericytes in animals maintained on high-galactose diets (Robinson et al., 1989). Also, in streptozocin-diabetic or fructose-fed rats the development of retinopathic changes was prevented by aldose reductase inhibitors (Kojima et al., 1985). In contrast, collagen synthesis by retinal pericytes was unaffected (Li et al., 1985). 

Fig. 1. The structures of key retinoids and their precursors. Fish convert retinyl esters (e.g. retinyl palmitate (RP)) and carotenoids (e.g. /3-carotene) to retinol in the gut lumen prior to intestinal absorption. Retinyl esters (e.g. RP) stored in the liver are synthesized from retinol by lecithin retinol acyltransferase (LRAT) and acyl CoAiretinol acyltransferase (ARAT). The retinyl esters are mobilized through their conversion to retinol by retinyl ester hydrolase (REH), which is then transported in the circulation to various sites in the body. Retinol is further metabolized within specific tissues to retinal by alcohol dehydrogenases (ADH) or short-chain dehydrogenase/reductase. Retinal is converted to the two major biologically active forms of retinoic acid (RA) (all-trans and 9-cis RA). Retinaldehyde dehydrogenase 2 (Raldh2) synthesizes all-trans RA from all-trans precursors and 9-cis RA form 9-cis precursors.

Tissue Location and Role of Aldose Reductase in Animal Models of Diabetic Complications. Aldose reductase (AR) has been located immunohistochemically in many tissues of the dog and rat, most notably, in corneal epithelium, retina, optic nerve, kidney papillae, aortic endothelium and smooth muscle cells as well as peripheral nerve and lens. AR has also been measured in human and monkey retinal mural cells. These cells are thought to provide the structural support for retinal capillaries and their loss is the first abnormality seen in clinical diabetic retinopathy. In addition, AR-like activity has been reported in a human retinoblastoma cell line and sorbinil inhibits this activity in these cells. Finally, a recent report has demonstrated that AR is present in isolated capillaries from bovine retina and cerebral cortex. Therefore, AR appears to be present in all tissues which are uniquely susceptible to deterioration during prolonged exposure to the hyperglycemia of diabetes. Accumulation of the products of the polyol pathway, sorbitol and fructose, has been demonstrated in these tissues and, where tested, sorbinil and other AR inhibitors have been shown to inhibit this accumulation. 

Sun W, Oates PJ, Coutcher JB, Gerhardinger C, Lorenzi M. A selective aldose reductase inhibitor of a new structural class prevents or reverses early retinal abnormabties in experimental diabetic retinopathy. Diabetes 2006 55 2757-2762. 

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