Chemical structure--teratogenicity relationships, toxicokinetics and metabolism in risk assessment of retinoids.

Retinoic acid, an oxidative metabolite of vitamin A, is involved in the control of many biological processes including embryonic development and excess as well as deficiency of retinoids has been found to be teratogenic. The effects of retinoids in normal as well as abnormal development may be mediated by two members of retinoid receptors, the RARs and RXRs, which exhibit specific temporal and spatial expression during development. Evidence accumulates that any alteration of this complex retinoid system may be related to teratogenic effects. Here we investigate the influence of toxicokinetic parameters, including aspects of metabolism and placental transfer, on the teratogenic potency of retinoids. It is demonstrated that activation (oxidation of retinoic acids; hydrolysis of glycoconjugates) and deactivation reactions (isomerization from trans- into cis-configuration; beta-glucuronidation) relate to teratogenesis. The beta-glucuronides of retinoic acids show poor placental transfer and prolonged presence in the maternal organism. Non-retinoid compounds such as antiepileptic agents may exert some of their teratogenicity via alteration of endogenous retinoid levels.

Comparative assessment of the toxicology of vitamin A and retinoids in man.

As the title implies, any assessment of the toxic effects of vitamin A derivatives must distinguish between vitamin A in the truest sense, i.e. retinol, and retinoic acid and its synthetic derivatives. Just as no single description is universally applicable to the mode of action of vitamin A derivatives, so too do their toxic effects defy generalization. The recommendation made in 1982 by IUPAC [Eur. J. Biochem., 129 (1989) 1] to designate all derivatives with the typical structure of the vitamin as being retinoids may be chemically logical and correct but, when it comes to describing the effects and side-effects of vitamin A derivatives, it leads to misunderstandings. Retinol, which is frequently used as synonym for vitamin A, can eliminate all symptoms of vitamin A deficiency if it is taken in sufficient quantity with the diet. The term retinol will therefore be used here as a synonym for vitamin A whereas retinoic acid and its derivatives--including the synthetic ones--will be referred to as retinoids because they do not cover the whole spectrum of effects exerted by retinol and because they also vary markedly in their side-effects. In contrast to the nomenclature proposed by IUPAC, this system provides a clear and logical distinction for describing biological processes. Other authors have favoured it in recent times [Chytil, F., J. Am. Acad. Dermatol., 15 (1986) 741; Olson, J.A., Semin. Oncol., x (3) (1983) 290; Olson, J.A., Am. J. Clin. Nutr., 45 (1987) 704; Zbinden, G., Acta Dermatovener., 74 (1975) 36]. By vitamin A, therefore, is meant all derivatives that can possibly originate from retinol in the organism. This also covers the small quantities of retinoic acid formed from retinol. On the other hand, by retinoids is meant the natural retinoic acid derivatives and their synthetic forms in their special modes of action. Since retinoic acid cannot be reduced to retinol in the organism, this nomenclature provides a clear demarcation within the biological system. Vitamin A is essential to the growth and development of higher life forms and functions in many different ways within the organism. Although vitamin A was one of the first vitamins to be described, even today there is still some uncertainty as to its mode of action, with the exception of that of retinal (vitamin A aldehyde) in vision.(ABSTRACT TRUNCATED AT 400 WORDS)

The roles of vitamin A in the prevention of neoplastic diseases: a critical assessment.

The role of vitamin A and its analogs (retinoids) in the prevention and therapy of neoplastic diseases is discussed. Epidemiological data showing a relationship between vitamin A deficiency and increased frequency of tumors in man and animals are examined and the experimental models demonstrating the protective action of retinoids in the respect of both spontaneous and induced neoplasias of animals are reviewed. Among the possible mechanisms responsible of the antineoplastic activity, the immunopotentiating effect is underlined. Some toxicological aspects of retinoids administration and the consequent application of the experimental results in human medicine are finally discussed.