Retinol metabolites

An alternative approach to determining requirements is to measure the fractional rate of catabolism of the vitamin by use of a radioactive tracer, then determine the intake that would be required to maintain an appropriate level of liver reserves. As discussed in Section2.2.1.1, when the liver concentration rises above 70 /rmol per kg, there is increased activity of the microsomal oxidation of vitamin A and biliary excretion of retinol metabolites. The fractional catabolic rate is 0.5% per day assuming 50% efficiency of storage of dietary retinol, this gives a mean requirement of 6.7 /rg per kg of body weight and a reference intake of 650 to 700 /rg for adult men (Olson, 1987a). Reference intakes for vitamin A are shown in Table 2.4. 

As the intake of vitamin A increases, there is an increase in the excretion of metabolites in bile, once adequate liver reserves have been established. However, the biliary excretion of retinol metabolites reaches a plateau at relatively low levels, and it seems likely that this explains the relatively low toxic threshold (Olson, 1986). Vitamin A intoxication is associated with the appearance of both retinol and retinyl esters bound to albumin and in plasma lipoproteins, which can be taken up by tissues in an uncontrolled manner the amount of circulating retinol bound to RBP does not increase. Retinol has a membrane lytic action it was noted in Section 2.2.2.3 that one of the functions of RBP binding seems to be to protect tissues against retinol, as well as to protect retinol against oxidation (Meeks et al., 1981). 

Chen AC, Guo X, Derguini F, Gudas LJ (1997) Human breast cancer cells and normal mammary epithelial cells retinol metabolism and growth inhibition by the retinol metabolite 4-oxoretinol. Cancer Res 57 4642-4651... 

Reactions of lithiated dimethyl cyclohex-2-enylphosphonate (775) with aldehydes were studied and determined to proceed with a or 6 regio-selectivity. Such an unusual regioselectivity resulted from the contribution of two allylic carbanions one, stabilised by the phosphonate moiety and the other stabilised by the carboethoxy group. The products of the Horner-Wadsworth-Emmons reaction, including an analogue of some retinol metabolites (776), were formed under kinetic conditions whereas the 5-adduct (774) with benzaldehyde was obtained as a thermodynamic product (Scheme 197). °... 

Arnhold, T, Ehnazar, M.M.A., and Nau, H., Prevention of vitamin A teratogenesis by phytol or phytanic acid results from reduced metabolism of retinol to the teratogenic metabolite, all frara-retinoic acid, Toxicol. Sci., 66, 274, 2002. 

In intestinal cells, carotenoids can be incorporated into CMs as intact molecules or metabolized into mainly retinol (or vitamin A), but also in retinoic acid and apoc-arotenals (see below for carotenoid cleavage reactions). These polar metabolites are directly secreted into the blood stream via the portal vein (Figure 3.2.2). Within intestinal cells, retinol can be also esterified into retinyl esters. 

The central cleavage of P-carotene 1 is most likely the major pathway by which mammals produce the required retinoids il), in particular, retinal 2, which is essential for vision and is subsequently oxidized to retinoic acid 3 and reduced to retinol 4. An alternative excentric cleavage of 1 has been reported involving scission of the double bond at C7-C8 producing P-8 -apocarotenal 5 (2a,2b) which is subsequently oxidized to 2 (Fig. 1) (2c). The significance of carotene metabolites such as 2, 3 and 4 to embryonic development and other vital processes such as skin and membrane protection is a major concern of medicinal chemistry. 

Metabohc derivatives of the fat-soluble vitamin retinol, which was first described in 1913. These metabolites play a central role in the visual process where the primary photoevent is attended by conversion of ll-cA-retinal to all-rrans-retinal. The oxidized metabolite retinoic acid is an agonist in cell growth and proliferation. 

D2. De Luca, L., Rosso, G., and Wolf, G., The biosynthesis of a mannolipid that contains a polar metabolite of 15- C-retinol. Biochem. Biophys. Res. Commun. 41, 615-620 (1970). 

This class includes both vitamin A and the provitamin A carotenoids. All the compounds related to all-trani-retinol (Figure 19.11) are known as vitamin A. These compounds, together with their metabolites and synthetic derivatives, exhibiting the same properties are called retinoids. Vitamin A is found in animal products as retinyl esters (mainly palmitate). 

Dietary vitamin A is stored in the liver and secreted into the bloodstream when needed. The circulating retinol is taken up by target cells and oxidized in part to retinoic acid, which induces the synthesis of proteins through the direct control of gene expression. This type of action—gene activation—establishes vitamin A (in the form of its metabolite, retinoic acid) as a hormone, similar to the steroid hormones and the thyroid hormone. 

The A group of vitamins are important metabolites of carotenoids. Vitamin A, (retinol) (Figure 5.70) effectively has a diterpene structure, but it is derived in mammals by oxidative... 

Retinoic acid is a metabolite of retinol in the liver, intestine, and bile of rat, and of retinyl acetate in the kidney and blood,378 and studies have been reported concerning the metabolism of retinoic acid and of vitamin A in various tissues of rats that are deficient in vitamin A.379... 

The term vitamin A can include any compound with the biological activity of the vitamin provitamin A carotenoids, retinol, and its active metabolites. 

Metabolites of polychlorinated biphenyls bind to the thyroxine binding site of transthyretin and, in doing so, impair the binding of RBP. As a result of this, there is free RBP-bound retinol in plasma, which is filtered at the glomerulus andhence lost in the urine. This may account for the vitamin A depleting action of polychlorinated biphenyls (Brouwer and van den Berg, 1986). 

Brouwer A and van den Berg KJ (1986) Binding of a metabolite of 3,4,3, 4 -tetra-chlorobiphenyl to transthyretin reduces serum vitamin A transport by inhibiting the formation of the protein complex carrying both retinol and thyroxin. Toxicology and Applied Pharmacology 85,301-12. 

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