Retinyl esters synthesis

More than 90% of the body s supply of vitamin A is stored in the liver. The hepatic parenchymal cells are involved in its uptake, storage, and metabolism. Retinyl esters are transferred to hepatic fat-storing cells (also called Ito cells or lipocytes) from the parenchymal cells. The capacity of these fat-storing cells may determine when vitamin A toxicosis becomes symptomatic. During the development of hepatic fibrosis (e.g., in alcoholic liver disease), vitamin A stores in Ito cells disappear and the cells differentiate to myofibroblasts. These cells appear to be the ones responsible for the increased collagen synthesis seen in fibrotic and cirrhotic livers. 

In this introduction, we do not provide a more detailed review of the classical discoveries in the field of vitamin A research. As already discussed in part, these classical discoveries included the original description of fat-soluble A and the introduction of the term ""vitamin A the recognition of retinol as a substance distinct from its carotenoid precursors the development of quantitative chemical methods for the analysis and assay of retinol and related substances the elucidation of the chemical structure and then the total synthesis of retinol, retinyl esters, and retinoic acid the description of the unique pathology of both hypovitaminosis A and h q)ervitaminosis A in experimental animals and man the elucidation of the fundamental role of retinaldehyde in vision the determination of human and animal needs for retinol or its precursors for adequate nutrition and the development of practical syntheses for the commercial production of retinyl esters to meet those nutritional needs. This historical story has been... 

Zinc deficiency accompanied by a depression in plasma retinol has been noted in several studies. Some investigators have reported an increased liver vitamin A in several species of zinc-deficient animals (Stevenson and Earle, 1956 Saraswat and Arora, 1972 J. C. Smith et aL, 1973, 1976 Brown et aL, 1976 Jacobs et al., 1978 Carney et aL, 1976). There are also reports in humans in an association between lowered zinc, retinol, and RBP (Jacobs et a/., 1978 Solomons and Russell, 1980). J. C. Smith et al, (1973) suggested that hepatic mobilization of vitamin A was impaired by zinc deficiency and their follow-up studies demonstrated a depression in liver and plasma RBP in the zinc-deficient rat compared to pair-fed controls (Brown et al., 1976 Smith et al., 1974). The depression was hypothesized to be the result of a depressed synthesis rather than an increased turnover of RBP. That preformed RBP is present in zinc-deficient rats was demonstrated by Carney et al. (1976) using labeled vitamin A. Zinc-deficient rats, whether or not they were also vitamin A-deficient, were able to mobilize over a short time span a small oral dose of vitamin A as well as could their pair-fed controls. Those animals deficient only in zinc excreted metabolites of the labeled vitamin in a similar quantitative manner as the pair-fed controls for 6 days postdosing. These data suggest that the release of retinol from retinyl ester stores, as well as a depressed RBP synthetic rate, contributed to low plasma levels of vitamin A in zinc deficiency. 

In the dark-adapted eyes of most animals, the retinoid stores in the RPE represent between 1 and 6 mol Eq of the retinal visual pigment. It is not known whether the magnitude of these stores depends on the vitamin A status of the animal, although it is probable that they serve as a reserve that protects the visual system from retinoid depletion under conditions of dietary deficiency. Since these stores typically contain up to 75% 11-m-retinyl ester, the provision of 11-cis isomer for visual pigment synthesis may also be important under certain circumstances. However, the presence of this isomer in the RPE is not critical for regeneration, which can proceed efficiently in the absence of appreciable supplies of 11-cis-retinyl ester [see Bridges (1976b) for further discussion of this question]. 

It is likely that the ll-cis retinol is stored as the ester and therefore it would be expected that an 1 l-cis retinyl ester hydrolase would be present in the RPE. 1 l-cis Retinyl esters have been shown to be present in the RPE, particularly in the dark [68]. Mata et al. [69] have observed an 1 l-cis ester hydrolase. This enzyme has been colocalized with 1 l-cis retinyl esters in the plasma membrane of the RPE [70]. Interestingly, these results suggest a compartmentalization of the retinoid esters, as the site of synthesis of these esters is in the endoplasmic reticulum utilizing the enzyme lecithimretinol acyltransferase (LRAT) [71]. 

Enzymically synthesized retinyl palmitate had a lower peroxide value (POV = 2.5 mEq/ kg under Na gas) than that obtained by the conventional organic synthesis (43 mEq/kg under Na) as is shown in Table 5. In the case of retinyl oleate synthesis from retinyl acetate and oleic acid, a similar difference was observed between enzymic and organic syntheses the POV of retinyl oleate was 9.0 mEq/kg for enzymic synthesis under Na, which was one-twentieth as much as that for organic synthesis (200 mEq/kg under Na). Therefore, the synthesis of biologically interesting substances, such as eicosapentaenoic acid esters [62], will become possible under quite mild conditions by the use of enzymes such as PEG-lipase. 

The original work on which subsequent study and synthesis of retinoids are based was carried out by Karrer and Morf (1933) and Heilbron et al, (1932, 1948). In 1931 Karrer et aL were able to determine the structure of retinol (1) using a highly purified vitamin A extract that they had obtained from shark liver oil (von Euler and Karrer, 1931). Using such retinol preparations, the first oily retinol esters [for example retinyl acetate (9)] were prepared (Karrer et al., 1931 Heilbron et al., 1932). 

In the course of almost 50 years of synthetic retinoid chemistry up to the present time, a large number of processes for the synthesis of retinol (1) and its esters, such as retinyl acetate (9) and retinyl palmitate (113), have been developed. The most important large-scale industrial processes today are based on the work of Isler et al. at Hoffmann-La Roche, and of Pommer et al. at BASF. These two processes probably satisfy a large part of the world demand for retinol (1) (vitamin A), most of which is used for the production of animal feeds. 

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