Retinol mechanisms

Ethanol also inhibits ADH-catalyzed retinol oxidation in vitro, and ethanol treatment of mouse embtyos has been demonstrated to reduce endogenous RA levels. The inhibition of cytosolic RolDH activity and stimulation of microsomal RolDH activity could explain ethanol-mediated vitamin A depletion, separate from ADH isoenzymes. Although the exact mechanism of inhibition of retinoid metabolism by ethanol is unclear, these observations are consistent with the finding that patients with alcoholic liver disease have depletedhepatic vitamin A reserves [review see [2]. 

A small but variable proportion of the carotenoids with one or two P-ionone rings (mainly P-carotene) are cleaved in the enterocytes to produce retinol (vitamin A). This process is very tightly controlled, so that too much vitamin A is not produced, although the control mechanism is not clear. Some cleavage of P-carotene can also occur in the liver, but this does not account for the turnover of P-carotene in the body. Small amounts of carotenoids are subject to enterohepatic circulation, but this does not account for losses. 

During, A, and Harrison, EH, 2007. Mechanisms of provitamin A (carotenoid) and vitamin A (retinol) transport into and out of intestinal Caco-2 cells. J Lipid Res 48, 2283-2294. 

A normal-phase HPLC method was employed for the separation of 11 -cis- and all-frany-retinals. Separation was performed in a silica column (150 X 6.0 mm i.d. particle size 3 jum) with an isocratic mobile phase (n-hexane with 15 per cent ethyl acetate and 0.15 per cent ethanol). The flow rate was 1 ml/min and retinols were detected at 360 nm. The method separated well the 11 -cis- and all-/ran.v-retinals as demonstrated in Fig. 2.162. The results emphasize again the decisive role of chromatographic methods in the elucidation of the mechanism of various biochemical processes [334],... 

Adsorption chromatography is a powerful means of separating cis and trans isomers of unsaturated compounds, the separation mechanism being attributed to a steric fitting of solute molecules with the discrete adsorption sites. This is illustrated in the isocratic separation of six geometric isomers of vitamin A obtained by photolysis of all-fran.v-retinol (109). 

The lipase-catalysed hydrolysis of methyl 2-fluoro-2-arylpropionates was proposed to proceed via a mechanism whereby, after ester hydrolysis, the enzyme facilitates the elimination of fluoride ion with the formation of a carbocation stabilized by the adjacent C02 group.230 Determination of the crystal structure of human sialidase Neu2, an enzyme that catalyses the hydrolysis of sialic acids, reveals a tyrosine residue that is positioned in the active site to stabilize the carbocation proposed as an intermediate in the hydrolysis.231 ll-Fluoro-all-frans-retinol is found to undergo isomerization to its 11 -cis form in the presence of visual cycle enzymes, in contrast to a previous study where no isomerization was reported.232 The result of the prior study was taken as evidence for a carbonium ion pathway in the isomerization. Although the authors of the present study do not rule out such a mechanism, they suggest that the isomerization mechanism remains unknown. Data obtained in a study of the oxidation of... 

Vitamin A and its derivatives, the so-called retinoids (1 ), exert anti-tumor activity at a variety of organ sites in various animal model systems (2-8). Recent studies suggest that high serum levels of vitamin A (retinol) are related to a reduced tumor incidence in human populations (9-10), and that a high dietary intake of foods rich in vitamin A reduces tumor yield (11-14). Thus, there is considerable interest, and effort made in elucidating the mechanism by which vitamin A and retinoids exert anti-tumor activity. 

The Rhodonine chromophores consist of a family of twelve, four related to Retinol (Vitamin A1 and found in saline-based animals), four related to 3,4 dehydroietinol (Vitamin A2 and associated with the freshwater-based animals) and four related to 3-hydroxyretinol (Vitamin A3 and found primarily in the two-winged flies, the Diptera Order of Arthropoda). The functional absorption spectra of these three sets, when in the liquid crystalline state, are virtually identical. This is due to the primary quantum-mechanical mechanism involved and the identical form of their chromophoric structure. The members of each set are spaced at 95 2 nm. 

The first two of these roles appear to focus on the conformal chemistry associated with the external profile of the molecules. The latter role focuses on the internal, quantum-mechanical structure of the molecules. While retinol, in its metabolic role as a vitamin participates in the manufacture of components of the disks of the Outer Segment of the Photoreceptor cells, it primary role is the last one. It acts as the critical chromogen, independent of any vitamin or hormonal role, leading to the production of chromophores in the retinal pigment epithelium (RPE) cells of the eye. Morton noted this role specifically In the retina, retinol is indubitably a precursor. ... 

The Rhodonine family of chromophores, when in the liquid crystalline state and with an adequate de-excitation mechanism consists of four distinct chromophores based on retinol and four based on retinol2. These are the chromophores of animal vision and their application is pervasive. The presence of all four chromophores in chordate... 

Topical application of Cathepsin D-like enzyme from mushroom extract (Actizyme) has also been shown to be beneficial for the treatment of xerosis.47 In dry skin SC turnover is reduced. This parameter can be measured in vivo using the dansyl chloride test. Addition of this enzyme to a formulation increased SC turnover by about 30%. This was of similar order to the effect of hydroxyacids, retinol, and mechanical scrubbing. In contrast to these treatments use of the enzyme did not impair barrier function nor increase stinging scores. 

With the exception of photodissociation to radical ions observed for retinol in polar solvents (144), cis-trans isomerization is the major photochemical transformation undergone by all forms of the free retinyl-polyene chromophore. [Unidentified photochemical damage has been reported to occur with very low quantum yields, e.g., 0.04 in the case of all-trans retinal (177).] We shall subsequently see that critical comparisons between the photochemical behavior of the biopigments and that of the opsin-free chromophore have led to the conclusion that the protein moiety plays a major role in governing the photochemical mechanism in rhodopsin (176). It is, therefore, natural that in parallel to spectroscopic and theoretical investigations, considerable attention has been devoted to the photoisomerization of model compounds, particularly to that of retinal isomers. 

A variety of other tissues synthesize RBP this provides a mechanism for return to the liver of retinol in excess of requirements that has heen taken up from chylomicrons hy the action of Upoprotein lipase. Because these tissues do not synthesize transthyretin, the hinding of holo-RBP to transthyretin must occur in the circulation after release. 

The doses of retinol that are protective in animals are in the toxic range (Section 2.5.1) and are unlikely to be useful in cancer therapy or prevention. A number of synthetic retinoids have been developed, in a search for compounds that show anticancer activity, but are metabolized, stored, and transported differently, or bind to different subtypes of retinoid receptor and are less toxic. RXR-selective ligands are less toxic and more active in animal cancer models than RAR ligands (Lippman and Lotan, 2000). Fenretinamide, and possibly other retinoids that have antitumor activity, exerts at least part of its action by induction of apoptosis by a receptor-independent mechanism (Wu et al., 2001). 

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