Retinoid retinol systems

Mutagenesis induced in Salmonella typhimurium by 2-fluorenamine and other chemical carcinogens was inhibited by low levels of retinol and other retinoids when carcinogen activation was carried out by rat liver microsomes. In contrast, low levels of retinoids enhanced mutagenesis when carcinogen activation was mediated by whole liver homogenates. There was no effect of the provitamin 3-carotene in this test system. 

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. 

In no instance did the synthetic retinoid possess as great an inhibitory capacity as do retinol or retinyl acetate. In addition, the provitamin g-carotene had no effect on mutagenicity of 2-fluorenamine in Salmonella regardless of the carcinogen activation system (Tables III and IV). Thus, 3-carotene would apparently require enzymatic cleavage to vitamin A in order to have an effect in this ijri vitro bioassay and exerts no role by itself in modulating the metabolism of chemical carcinogens in the model system. 

This Chapter will present the actual chromophores of vision, labeled the Rhodonines and derivable from a number of feedstocks, including the retinol family, consist of relatively small molecules with a molecular weight of either 285 (R5 R9) or 299 (R7 R11). They are retinoids of the resonant conjugate type. They are also carboxylic-ion systems and exhibit a negative charge in their fundamental form. The molecules are relatively easily generated in the laboratory in pure form. However, they exhibit a number of unique properties that have made their isolation difficult. They only exhibit the properties of a visual chromophore when in the liquid crystalline state. Their absorption characteristic is a transient one unless a means of de-exciting the molecules of the liquid crystal is present. Finally, they are extremely sensitive to destruction by oxidants and alkali metal ions. 

Serum retinol-binding protein (RBP) is a retinoid-binding protein found in the circulatory system. The protein is synthesized in the hepato-cytes, where it accumulates until the presence of its ligand in the circulation triggers the secretion of the complex (Ronne et cd., 1983 Good-... 

Preformed vitamin A, most often in the form of retinyi ester, or carotenoids are subject to emulsification and mised micelle formation by the action of bile salts before being transported into the intestinal cell. Here the retinyi esters are moved across the mucosal membrane and hydrolyzed to retinol within the cell to then be reesterified by cellular retinol-binding protein II and packaged into chylomicra, which then enter the mesenteric lymphatic system and pass mto the systemic circulation. A small amount of the ingested retinoid is also converted into retinoic acid in the intestinal cell. The efficiency of absorption of preformed vitamin A is high at between 70% and 90%. ... 

Retinoids are compounds structurally related to retinol, more commonly known as vitamin A. The basic structure of vitamin A is that of a ditherpene with a hydrophobic ring on one end and an isoprenic side chain containing a polar hydroxyl group on the other. It has long been known that vitamin A has at least three distinct functions in supporting mammalian life systemic, optic and reproductive ones. 

Creech Kraft, J. Kimelman, D. Juchau, M.R. Xenopus Laevis A model system for the study of embryonic retinoid metabolism. I. Embryonic metabolism of 9-cis- and all-trons-retinals and retinols and their corresponding acid forms. Drug Metab.Dispos., 1995, 23, 72-82... 

Table I summarizes the FTCs for /3-carotene and retinol metabolism. Table I also summarizes the flow rates of /3-carotene and retinoid from donor to recipient compartments during steady state. As the mass of analyte in the system changes, the flows will also change, but the FTCs are expected to remain constant unless alternate pathways (mechanisms) for metabolism of the tracee are induced by the large dose of tracer.

Limb bud development is a good system in which to study the role of retinoids as morphogens. Retinoids are natural and synthetic compounds related to retinol and retinoic acid. Retinoic acid is formed by the oxidation of retinol (see Section 2.4.1), and both retinoic acid and the related metabolite 3,4-didehyd-roretinoic acid are present in the normal limb buds of chick embryos (Scholfield, Rowe Brickell, 1992),... 

The method that was used to identify tRA in the chick limb bud by Thaller and Eichele (3) is described below with only minor modifications, since it has been successfully used by several groups, including ourselves, to identify retinoids in the mouse embryo (5). An example of this type of chromatography is given in Fig. 2. Figure 2A shows the separation of a mixture of standards and Fig. 2B, the retinoids present in a mouse embryo. However, this method was developed before the discovery of 9-cis-RA, and it fails to separate this isomer because 9-cis coelutes with retinol, so this is by no means a perfect method. To identify 9-cis, we have developed a method (18) that involves first running the sample on a normal-phase system with an NH column that retains only the acids and then running the acid fractions on a reverse-phase system as described below. 

A number of other nuclear receptors have also been shown to bind and be activated by retinoids. For example, testicular receptor 4 (TR4) has recently been suggested to be a retinoid receptor, because the binding of both retinol and RA can induce conformational changes of TR4 leading to the activation of this receptor (Zhou et al. 2011). TR4 can either function as homodimer or heterodimerize with testicular receptor 2 (TR2) to function in spermatogenesis, hpid and hpoprotein regulation, and central nervous system development (Zhou et al. 2011). However, additional experiments are required to reveal the physiological and developmental implications of the activation of TR4 by retinoids, such as RA (Zhou et al. 2011). 

A large number of retinoids in which the cyclogeranyl ring of the natural retinoids has been replaced by a different ring system have been prepared using the reaction sequences previously developed for the synthesis of retinol (1),... 

In the continued search for retinoids with improved systemic tolerance, a variety of condensation products of retinaldehyde with aliphatic and alicyclic 1,3-diketones have been prepared (Acton and Brossi, 1980). Two representatives, the acetyl acetone and the dimedone derivative, have been prepared labeled with tritium (Kaegi et al., 1982c). As outlined in Fig. 15, dW-trans-retinol-11- H was produced by reduction of all- n -rctinoic-ll- H acid and then oxidized with manganese dioxide. HPLC of the resulting product showed... 

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