Paradoxal-allosteric mechanism action of retinoic acids, and teratogenicity theory

In this study, the paradoxical-allosteric effect of retinoic acids and the molecular mechanism of fetal anomalies developed through this effect was presented in the literature. With the advancement of developmental biology, the organogenesis process of the human embryo has been largely clarified. However, the molecular mechanism of congenital anomalies caused by some virus infections, drugs, and various chemical compounds has not been resolved. Although the etiological agents in fetal anomalies are well known, the mechanism by which these agents cause fetal anomalies has not been solved yet. It is known that vitamin A and retinoic acids play an important role in tissue and organ development and shaping during embryogenesis, and fetal anomalies occur with the deterioration of retinoic acid signal in the organogenesis period. Both deficiency and excess of vitamin A and its biological derivatives, retinoic acids, cause congenital malformations. Interestingly, these anomalies are the same in both vitamin A deficiency and vitamin A excess. Based on this, we can assume that retinoic acids have a paradoxical mode of action on fetal anomalies and other biological effects. We define the effect of both deficiency and excess of retinoic acids to cause fetal anomalies as the paradoxical mode of action of retinoic acids. Retinoic acids can control their own metabolism and biological effects through an allosteric mechanism through retinoic acid receptors. This activity, which is seen as positive and negative feedback, occurs in the form of negative feedback to protect the organism from toxic effects at high doses of retinoic acids. Here, high doses of retinoic acids bind to retinoic acid receptors, causing conformational changes in the receptors with an allosteric effect, thus rendering the receptors dysfunctional. We define this mode of action of retinoic acids as the allosteric mechanism of action of retinoic acids. Likewise, at high doses of retinoic acids, a negative feedback mechanism comes into play, thus protecting the organism from the toxic effects of retinoic acids. In this process, retinoic acid receptors undergo conformational changes with the allosteric effect and become dysfunctional, resulting in dysfunctions seen in the absence of retinoic acid in the cell. Likewise, when this process coincides with the organogenesis period of fetal life, it results in fetal organ anomalies. This mechanism will also guide us in the treatment of Differentiation Syndrome seen during APL treatment.