Retinoids deficiency effect

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. 

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. 

Retinoids are a family of naturally occurring and synthetic analogues of vitamin A. The skin of subjects deficient in vitamin A becomes hyperplastic and keratotic (phrynoderma, or toad skin). While natural vitamin A is occasionally employed therapeutically, synthetic retinoids are more effective and represent a major advance in dermatological pharmacotherapy. Retinoids have myriad effects on cellular differentiation and proliferation it is likely that nuclear retinoic acid receptors mediate these effects by activating gene expression in a manner analogous to receptors for steroid hormones and thyroid hormones. Despite a common mechanism of action, however, retinoids vary widely in their physiological effects. 

Vitamin A absorbs UV light between 300 and 350 nm. After acute exposure to UVA or UVB a dose-dependent decrease of vitamin A was shown in mouse59 and humans.84 UV irradiation markedly reduced mRNA and protein of the nuclear retinoid receptors RARy and RXRa in humans and led to a near loss of retinoic acid induction of the RAR/RXR target genes and the cellular retinoic acid binding protein II thus effectively causing additionally a functional vitamin A deficiency.85... 

Retinoic acid modulates gene expression and tissue differentiation, acting by way of nuclear receptors. Historically, there was confusion between the effects of deficiency of vitamins A and D by the 1950s, it was believed that the confusion had been resolved. Elucidation of the nuclear actions of the two vitamins has shown that, in many systems, the two act in concert, forming retinoid-vitamin D heterodimeric receptors hypervitaminosis A can antagonize the actions of vitamin D. 

Retinoids in Cancer Prevention and Treatment Since the discovery of vitamin A, the observation that the main effects of deficiency are hyperplasia and loss of differentiation of squamous epithelium has raised speculation that the vitamin may he associated with carcinogenesis. Either deficiency may be a risk factor for cancer or increased intake may be protective. Deficient animals develop more spontaneous tumors and are more sensitive to chemical carcinogens, whereas liver reserves of vitamin A are lower in patients with cancer than in controls. One of the genes repressed by retinoic acid is the myc-oncogene. 

As detrimental effects result from deficiency as well as an excess of retinoids and carotenoids, and since both have similar adverse effects in terms of fibrosis, carcinogenesis, and possibly embryotoxicity, therapeutic measures must pay attention to the narrow therapeutic window, especially in drinkers, in whom alcohol narrows the therapeutic window even further by promoting the depletion of retinoids and by potentiating their toxicity (91). 

A terminal carboxylic add group is necessary for receptor affinity. (R2) was devoid of ability to bind to any receptor and (R30) exhibited RARa and RAR affinities 10- and 4-fold less, respectively, than that of (Rl) [88]. While activation of RARs by retinol has been reported to be much less effective than by retinoic add, retinol has recently been reported as a potent and rapid (30 min) inducer of transcription of the RARa gene in vitamin A-deficient rats [100]. Possibly, retinoid defidency sensitizes rat... 

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