In-vitro teratogenicity of retinoids.
Mid-gestation rat conceptuses were cultured for 48 h in serum containing the retinoids all-trans-retinoic acid (TRA), 13-cis-retinoic acid (13-CRA), etretinate (ETR), etretin or one of six retinamides at concentrations ranging from 0.5 to 400 micrograms/ml. TRA was toxic at a concentration of 0.5 microgram/ml. 13-CRA and etretin caused abnormal development at 1.0 microgram/ml. However, the six retinamides were less toxic and adverse developmental effects were only evident at concentrations of 50 or 100 micrograms/ml. ETR was without effect at 100 micrograms/ml, the highest dose level of this compound tested. In vivo, TRA, 13-CRA and ETR are highly teratogenic. In this culture system, TRA and 13-CRA caused abnormal development at very low concentrations but in contrast, ETR was non-toxic at 100 micrograms/ml. Therefore these findings indicate that in vivo, maternal pharmacokinetics, and bioactivation in particular, play a major role in inducing abnormal development. Cis/trans isomerization was not a major determinant of toxicity. However, there appeared to be a relationship between abnormal development and the actual or estimated pKa values of the 10 retinoids tested.
D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000187:drug effects; D066298:In Vitro Techniques; D017880:Limb Deformities, Congenital; D009436:Neural Tube Defects / Q000139:chemically induced; D014176:Protein Biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains; D012176:Retinoids / Q000633:toxicity*; D013723:Teratogens
D012176:Retinoids; D013723:Teratogens