YOU ARE NOW CONNECTED TO THE TOXLINE (1981 FORWARD, NON-ROYALTY) FILE. ==ICHTYOSIS== 1 AUTHOR Czarnetzki BM TITLE The pharmaceutical development of retinoids -- risks and challenges. SOURCE Teratology 1989 Sep;40(3):274 ABSTRACT The therapeutic efficacy of high oral doses of vitamin A and of vitamin A acid (all-trans-retinoic acid) have been studied by dermatologists in various cutaneous diseases such as acne, psoriasis, ichtyosis and cutaneous malignancies since the 1940ies. Although initial results were encouraging, various side effects of the hypervitaminosis A syndrome, particularly severe headache, limited an extensive use of these agents in the clinic. Urged by the medical community, Hoffman La-Roche therefore initiated a chemical synthesis program with the aim to find compounds with a more favorable therapeutic efficacy and side effect profile. These efforts resulted in the discovery of 13-cis retinoic acid in 1969 and of etretinate in 1972. In Europe, the registration of 13-cis retinoic acid for the treatment of severe cystic acne occurred later than that of etretinate for the treatment of disorders of keratinization since there were major concerns regarding the use of a teratogenic drug in the young acne patient population. Although both retinoids have revolutionized the treatment of cystic acne and of severe disorders of keritinization respectively, the risk/benefit ratio of these drugs is quite high, particularly with regard to the teratogenicity risk which is difficult to eliminate entirely due to improper use of the drugs by the patients and physicians. Enormous research efforts, with only minor success, have been extended so far to obtain chemical analogues of the currently available retinoids with a more favorable therapeutic index. These endeavors have received recently new impetus due to the discovery of the nuclear receptors for vitamin A acid. 9 AUTHOR Kochhar DM TITLE Retinoids and retinoid receptors in teratogenesis. SOURCE Senten Ijo 1995 Mar;35(1):55-71 ABSTRACT There is overwhelming evidence that vitamin A (retinol), presumably through its metabolite retinoic acid, participates in organogenesis at several stages and sites during normal development. Besides the important role of retinol and retinoic acid (RA) as micronutrients in growth and development, these retinoids and their synthetic analogs are now viewed as drugs for treatment of oncologic and dermatologic diseases. An excess of vitamin A, RA, or several other synthetic analogs are teratogenic. Mechanisms involved in teratogenesis remain unsolved but are under active investigation in many laboratories. The attention has recently focused on a series of endogenous proteins which serve as nuclear receptors for natural retinoids as means to discover how retinoids intervene in diverse cellular functions and which of their cellular and molecular targets are crucial to the developing embryo. There are two classes of receptors, termed retinoic acid receptors (RARs) and retinoid X receptors (RXRs). This brief review summarizes the results of our recent studies which suggest that: 1) the teratologic effects of retinoids are mediated by nuclear receptors; 2) the heterodimer RXR/RAR pathway is the major mechanism for the induction of teratogenesis; 3) RXR-selective synthetic retinoids have diminished teratogenicity; and 4) an overexpression of specific RARs in response to RA disrupt skeletal morphogenesis resulting in limb reduction defects. 10 AUTHOR Kochhar DM TITLE Developmental role of toxicity of retinoic acid. SOURCE Teratology 1994 Dec;50(6):4B ABSTRACT Vitamin A is an essential micronutrient indispensable in vision, growth and developmental processes, and cell differentiation. Oxidative metabolism of vitamin A in the body tissues yields several metabolites; two of these, namely all-trans retinoic acid (RA) and 9-cis RA, serve as hormones which mediate many of known functions of vitamin A. Vitamin A deficiency or excess is teratogenic in mammals. Precise mechanistic explanation for the teratogenic response is not clear but will be rewarding since several environmental factors disturb vitamin A status in the body and may, therefore, contribute to the burden of developmental defects through such a mechanism. Our effort is focused on understanding how do vitamin A and its metabolites cause maldevelopment. Based on preliminary evidence there is a high likelihood that the teratogenic effects of retinoids occur through a cascade of gene activation influenced or controlled by retinoid receptor proteins which reside in the nucleus and bind with high specificity certain vitamin A metabolites such as all-trans RA and 9-cis RA. These nuclear receptors belong to the steroid/thyroid hormone receptor super-family and are called retinoic acid receptors (RARs -- RAR-alpha, RAR-beta, RAR-gamma) and retinoid X receptors (RXRs -- RXR-alpha, RXR-beta, RXR-gamma). In preliminary studies, we found that retinoid exposure of mouse embryos at midgestation resulted not only in a dramatic enhancement in the synthesis of certain receptors in susceptible tissues but that a set of five other genes were also differentially activated in the same tissues. The identities or the functions of these genes are currently unknown. Our goals are to assess the role(s) of RARs and RXRs in vitamin A-induced teratogenesis and further to identify and characterize the function of genes expressed in target organs of abnormally developed embryos.