Retinoids deficiency

The retinoid toxicology of fish is a new subject, with only a decade s worth of research. The reduction of retinoid stores with toxicant exposure has been well documented however, the mechanism of this reduction and the implications on RA and fish physiology and health have not been determined. This is partially due to the lack of technology that would allow the easy measurement of RA in fish tissues (required in some remarkably small tissue samples compared to mammals ). It is very important for future studies to establish whether reductions of stored retinoids alter RA levels and whether changes in RA are responsible for the effects of a toxicant observed in fish. However, this may be a challenge in that long-term studies (months to years) may be required to induce retinoid deficiency in fish. 

Gale, E., Zile, M., Maden, M. 1999. Hindbrain respecification in the retinoid-deficient quail. Mech. Dev. 89, 43-54. 

Reversal of keratinization in retinoid-deficient hamster trachea (ED50, M)... 

D. Reversal of Keratinization in Retinoid-Deficient Hamster Tracheas... 

Another set of reactions involving retinol that has been studied in liver concerns the formation of retinyl phosphate and of retinyl phosphomannose conjugates. These studies have been directed toward the hypothesis that retinoid-containing glycolipids serve as intermediates for specific glycosylation reactions. It is well established that the biosynthesis of some glycoproteins is markedly decreased in a number of tissues in retinoid deficiency, and that glycoprotein... 

The existence of biologically active metabolites of retinoic acid has been reported. Krishnamurthy et al. (1963) detected a fat-soluble metabolite of retinoic acid, which displayed biological activity in a rat curative assay, in the liver of chicks administered a 10-mg oral dose of the parent retinoid. Similarly, Wolf et al. (1963) reported that an intestinal metabolite, isolated from retinoid-deficient rats injected with labeled retinoic acid, was active in restoring to normal levels the mucopolysaccharide biosynthesis in retinoid-deficient rat intestinal cell-free particle suspensions. The same laboratory also described a decarboxy-lated metabolite of both retinol and retinoic acid that was isolated from the intestine of retinoid-deficient rats administered retinol or retinoic acid. This compound, which appeared to have both carboxyl and hydroxyl functional groups, was biologically active in a growth assay (Yagishita et al., 1964). In... 

Zile and DeLuca reported the existence of a metabolite of retinoic acid that was found in rat liver and that was able to support the growth of retinoid-deficient rats. This metabolite was later identified as 13-a.r-retinoic acid (E6) and most, if not all, of it appeared to be generated from all-rrans-retinoic acid by the extraction procedure (Emerick et al., 1967). Sundaresan (1966) has likewise reported diat an acidic metabolite of retinoic acid extracted from normal rat liver was able to restore to near normal the activity of a sulfur-activating enzyme (ATP-sulliiiylase) whose activity was depressed in retinoid-deficient rat liver supernatants. Except for the 13-c/s-retinoic acid, none of these metabolites have been characterized further. 

Retinoid-deficient hamsters were pretieated with all-rram-retinoic acid or retinyl acetate 3 days prior to sacrifice. Microsomes were prepared and in vitro metabolism of retinoic acid was performed as described by Roberts et al, (1979a,b). 

Before considering the effects of retinoids on isolated cellular systems, either in organ culture or cell culture, we briefly note some of the marked effects that retinoid deficiency or excess has on the developing embryo. For many years, retinoids have been known to be potent teratogens and an extensive summary of their teratogenic effects can be found in review articles (Kalter and Warkany, 1961 Kochhar, 1967, 1968 Shenefelt, 1972 Spom eta/., 1981) and in Chapter 13. Apart from the clinical importance of these phenomena, they may also provide valuable clues relating to the mechanism of action. 

Possibly in support of the first hypothesis. Rosso et al. (1981) have shown that retinoid-deficient rats accumulate an oligosaccharide-lipid of the composition Man5(GlcNAc)2PPDol (reaction 2, Fig. 1), and that this shortened intermediate is rapidly replaced by the normal intermediate GlCjManglGlcNAcljPPDol upon treatment of the rats with retinyl acetate (reactions 3 and 4, Fig. 1). One interpretation of these data is that MRP might function in the synthesis of the oligosaccharide-lipid intermediate or that either retinoids or MRP, specifically, affect the activity of the MDP-dependent mannosyltransferase. In further support of this mechanism, De Luca et al. (1982) have demonstrated an accumulation of... 

---