Teratogenicity of Retinoids

G. Klopman and M. I. Dimayuga, J. Comput.-Aided Mol. Design, 4, 117 (1990). Computer Automated Structure Evaluation (CASE) of the Teratogenicity of Retinoids with the Aid of a Novel Geometry Index. 

Klopman G, Dimayuga ML. Computer Automated Structure Evaluation (CASE) of the teratogenicity of retinoids with the aid of a novel geometry index. Journal of Computer-Aided Molecular Design. 1990 4(2) 117-130. 

As discussed in a previous section, the systemic and topical toxicity, as well as the teratogenicity of retinoids, limits the clinical usefulness of these compounds. The general opinion of both basic scientists and clinicians is that these toxicities may be mitigated by the development of receptor subtype-selective retinoids. Although this may ultimately be proven to be true, there is currently little factual basis for this opinion, at least with respect to the RAR subtypes, because it has been quite difficult to separate clinical efficacy from toxicity. Nonetheless, this remains a noble goal in the continued development of receptor sub-type-selective retinoids. 

Jiang H, Penner JD, Beard RL, Chandraratna RAS, Kochhar DM (1995) Diminished teratogenicity of retinoid X receptor-selective synthetic retinoids. Biochem Pharmacol 50 669-676... 

Embryotoxicity/teratogenicity is the major drawback in the therapeutic use of retinoids. The exposure of the fetus during the first trimester with oral retinoids is known to produce characteristic malformations.93 There have also been case reports about malformations associated with retinoid embryopathy after the mother had used tretinoin topically during the first trimester of pregnancy 94-96... 

Retinoids (e.g. retinoic acid) are involved in development and in metabolic regulation (e.g. through induction of expression of PEPCK, the rate limiting enzyme in gluconeogenesis). Retinoic acid derives from retinol, which in turn derives from ingestion of plant a-, 3- and "/-carotenes and other carotenes. Retinoic acid acts via retinoic acid receptors and retinoid X receptors note that these receptors can heterodimerize in the nucleus with other related hormone receptors such as PPA-Rs. The developmental importance of retinoic acid is underscored by the teratogenicity of retinoic acid and other vitamin A related compounds, notably some compounds developed for anti-acne properties. 

Studies with knockout mutant mice lacking one or another of the retinoid receptors suggest that there is some degree of redundancy or overlap between the receptor subtypes, and that RARy is especiallyimportant in the teratogenic actions of retinoids (Section 2.5.1.1 Mark et al., 1999 Maden, 2000) ... 

There are few data about the safety of topical retinoids during pregnancy. The risk of teratogenicity of topical tretinoin, if any, appears to be minimal (SEDA-18, 164) (109). However, there is a case report (110). 

Non-teratogenic, adverse effects of retinoids are also severe and are dependent on route of administration and the nature of the disease being treated. Untoward effects of retinoid compounds administered by mouth are similar to those of hypervitaminosis A and include cheilitis and pronounced lipid disturbances such as hypertriglyceridemia, hypercholesterolemia, and reduction in high density lipoprotein levels, pancreatitis, vasculitis, con-... 

Kamm, J.J. (1982) Toxicology, carcinogenicity, and teratogenicity of some orally administered retinoids. Journal of the American Academy of Dermatology, 6 (4 Pt 2 Suppl),... 

Acute retinoid toxicity is similar to vitamin A intoxication. Side effects of retinoids include dry skin, nosebleeds from dry mucous membranes, conjunctivitis, and hair loss. Less frequently, musculoskeletal pain, pseudotumor cerebri, and mood alterations occur. Oral retinoids are potent teratogens and cause severe fetal malformations. Because of this, systemic retinoids should be used with great caution in females of childbearing potential. 

Toxicity studies of retinoids have involved assessment of teratogenic potential [104,105] and overall toxic effects [63,64] in adult animals upon treatment with retinoids. In general, it appears that the structural features necessary for teratogenic potency overlap with those features required for anti-cancer activity [105]. These requirements may be summarized as follows (1) An acidic polar terminus is necessary. (2) Conjugation in the three double bonds nearest to the polar terminus must be maintained. Unsaturation of the 7,8 double bond is not indispensable. (3) Substitution of non-polar groups in the terminal ring is required. 

Some retinoids are very irritating to the skin, and some are highly teratogenic. Hence when large amounts of retinoids are handled, adequate care should be taken so that neither solid particles nor solutions come into contact with the body. Because retinoids are lipid soluble, organic solvents are used to dissolve them. If a solution of retinoid falls on the body, the solvent quickly evaporates, and the retinoid is absorbed by the skin. Therefore, it is recommended that gloves be worn while working with retinoids. 

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. 

The use of etretinate either alone or in combination with presently available therapies for psoriasis has been very effective, especially for the typically treatment-resistant pustular and erythrodermic varieties. Unlike isotretinoin in acne, maintenance therapy with etretinate is necessary for most psoriatic patients. This raises questions about the long-term safety and the potential for teratogenicity of this retinoid. So far, no serious toxicity has been observed in patients who have received etretinate for 6 years. 

Howard WB, Willhite CC (1986) Toxicity of retinoids in humans and animals. J Toxicol-Toxin Rev 5 55-94 Gunning DB, Barua AB, Olson JA (1993) Comparative teratogenicity and metabolism of al -trans retinoic acid, SiW-trans retinoyl p-glucose, and a -trans retinoyl p-glucuronide in pregnant Sprague-Dawley rats. 

The toxicology, teratogenic profile and mechanism of retinoid action have been reviewed [1, 11, 18-20]. Among the drawbacks to currently approved retinoids, 13-cw-retinoic acid... 

Elmazar MMA, Ruhl R, Reichert U, Shroot B, Nau H (1997) RARa-mediated teratogenicity in mice is potentiated by an RXR agonist and reduced by an RAR antagonist Dissection of retinoid receptor-induced pathways. Toxicol Appl Pharmacol 146 21-28... 

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