Retinoic acid teratogenic effects

Systemically administered retinoids such as isotretinoin (1, Accutane ) have several disadvantages such as a relatively narrow therapeutic index and a variety of toxic effects including teratogenicity. Topically administered retinoids may avoid some of those drawbacks. For instance, tazarotene (2, Tazorac ) is a topical receptor-selective retenoid that normalizes differentiation and proliferation of keratinocytes. Its major metabolite, tazarotenic acid (11), binds to retinoic acid receptors (RARs) with high affinity. 

Much recent interest has been aroused by the fact that retinoid compounds, including both retinol and retinoic acid, reduce the incidence of experimentally induced cancer. In addition, 13-czs-retinoic acid taken orally is remarkably effective in treatment of severe cystic acne. s However, both vitamin A and retinoic acid in large doses are teratogenic, i.e., they cause fetal abnormalities. The use of 13-cis-retinoic acid during early phases of pregnancy led to a high incidence of major malformations in infants born.1 11 1... 

RARa mice show the same teratogenic effects of retinoic acid excess as wild-type mice. 

After administration of a -trans-, 3-cis- or 9-cw-retinoic acid, the respective retinoyl glu-curonides (RAG) have been identified as the major metabolite in most mammal models including the human system. Like R A, RAG is biologically active in promoting the growth of vitamin A-deficient rats [187] and in the induction of differentiation of, e. g., HL-60 cells [188], but unlike RA, RAG is less cytotoxic and teratogenic. Like RA, RAG is also effective in the topical treatment of human acne [189], but unlike RA, it does not produce any side effects associated with RA therapy [189]. 

Although retinoic acid and other retinoids are not very useful as vitamin A substitutes in the diet, they have been found to posses therapeutic value in treating dermatologic conditions. Nevertheless, an important side effect has been found in these compounds, they have teratogenic effects [16]. In view of this, It is important to determine which structural features in retinoids are related to teratogenicity in order to design a useful retinoid without this side effect. Some studies in this direction have been seen performed in another theoretical context [15],... 

Retinoic acid, available as an oral commercial preparation for the treatment of severe cystic acne (Accutane) has been one of the great successes in dermatology. However, it is not without side effects, some of which are severe. Oral retinoids are potent teratogens, and approximately one-fourth of all exposed fetuses develop birth defects. Their teratogenic potential has led to strict guidelines governing their use in women of child-bearing potential. Other side effects, such as elevated liver function tests, elevated serum lipids, and nyctalopia have also limited their use (43). 

Geraudie, J., Brulfert, A., Monnot, M. J., and Ferretti, P. (1994) Teratogenic and morphogenetic effects of retinoic acid on the regenerating pectoral fin in zebrafish. 

Anti-acne creams have been shown to cause systemic toxic effects. For example, retinoic acid is a known teratogen (Steele et al. 1983) and is found in certain formulations. Other formulations contain clindamycin, which is reviewed below. 

There are anecdotal reports of the efficacious use of oral 13-cfs-retinoic acid (isotretinoin) which, if instituted early, may prevent cyst formation. Isotretenoin 0.3-1 mg/kg/day may be indicated in severe cases for a course of 20 weeks. The drug should be administered only by those experienced in its use and in strict accordance with current prescribing instructions. The hepatotoxicity and lipid abnormalities sometimes associated with chloracne are theoretical reasons to avoid isotretinoin. Isotretinoin is a potent teratogen with other potentially significant side effects that require close monitoring (Gawkrodger 1991). 

Analysis of teratogenic effects of retinoic acid. Teratology, 7 289-298. 

Zhang, Z. Y., J. E. Balmer, A. LovUe, S. H. Fromm, and R. Blomhoff. 1996. Specific Teratogenic Effects of Different Retinoic Acid Isomers and Analogs in the Developing Anterior Central Nervous System of Zebrafish. Dev Dynam 206, no 1 73-86. 

Luo, J., Pascen, P, Conlon, R A, Rossant, J, and Gigudre, V. (1995) Mice lacking all isoforms of retinoic acid receptor beta develop normally and are susceptible to the teratogenic effects of retinoic acid Mech Dev 53,61-71... 

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