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Copyright by Eunyoung Park 2007 - The University of Texas at Austin

Copyright by Eunyoung Park 2007 - The University of Texas at Austin

chylomicrons (33).

chylomicrons (33). Retinol is de-esterified and excreted from the liver and circulates in the blood as a retinol binding protein (RBP)-retinol-transthyretin complex. Retinol is dissociated from RBP and delivered to cells. The mechanism of retinol transport from plasma to cytoplasm is still unclear. Intracellularly, retinol is bound to cellular retinol binding protein (CRBP). There are three CRBPs; CRBP I, expressed in the liver, kidney and eye, CRBP II, mainly expressed in the small intestine, and CRBP III, expressed in the heart, muscle, adipose and mammary tissues [For a review please see:(34)]. Retinol is converted to either retinyl esters for storage by lethicin:retinol acyltransferase (LRAT) in the intestine or acyl-CoA-retinol acyltranserase (ARAT) in the liver, mammary gland, or adipose tissue or to retinaldehyde as an intermediate form before metabolism to ATRA by alcohol dehyrogenase (ADH) or retinol dehydrogenase (ROLDH). Retinaldehyde is further metabolized to ATRA by retinal dehydrogenase (RALDH) (Fig. 1.2). CRABP I catalyzes the degradation of ATRA to all-trans-4-oxo-retinoic acid to lower the active intracellular ATRA concentrations (35). On the other hand, CRABP II transports ATRA to the nucleus where it interacts with retinoic acid receptors (RAR). The action of ATRA is mediated by nuclear RAR and retinoid X receptor (RXR), each consisting of three receptor types, α, β and γ. The heterodimer of RAR and RXR with ligand regulates ATRA-mediated gene transcription by binding to retinoic acid response elements (RAREs) [for review see: (36)]. RAREs are cis-acting elements in the promoter regions of retinoid-responsive genes composed of direct repeats (DR) of the consensus half-site sequence AGGTCA separated by five nucleotides. For example, 7

ATRA induces the expression of the RARβ through this mechanism regulating cell proliferation, growth and survival (37,38). 3. COLON CANCER AND RETINOL As mentioned above, ATRA is thought to regulate most of the effects of retinoids, via the ATRA/RAR/RXR/RARE pathway. Unfortunately, the period of inhibitory effect of ATRA on colon cancer is short due to acquisition of resistance to ATRA. ATRA resistance frequently occurs during cancer progression. ATRA-resistance is due to a defect in RAR α, β, or γ induction in response to ATRA [for review see: (31,39-41)]. The defective receptor varies with cell line but RARβ expression is frequently lost because of methylation of the RARE on the RARβ promoter region (39-42). Dietary retinyl-esters are converted to retinol in the intestinal lumen. The intestinal lumen, including colonocytes, is primarily exposed to retinol. Thus, dietary vitamin A supplementation can elevate retinol levels in the colon. Once absorbed, retinol is esterified and transported to the liver, the major site of vitamin A storage. Although serum retinol levels in non-vitamin A deficient animals vary from 1-2 μM, regardless of supplementation status, [for a review please see: (43)], hepatic retinol levels increase in response to supplementation and values in excess of 90 μM have been reported (44). Therefore, retinol could potentially be used to treat not only primary colon tumor growth but also liver metastases. Retinoids have been shown in numerous experimental situations to act as cancer chemopreventive and therapy agents [for review see: (30-32)]. Retinol, 9-cis-retinoic 8

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