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In-vitro teratogenicity of retinoids.

C E Steele, R Marlow, J Turton

    British Journal of Experimental Pathology
    |April 1, 1987
    PubMed
    Summary

    Retinoids like all-trans-retinoic acid (TRA) and 13-cis-retinoic acid (13-CRA) are toxic to developing rat embryos in culture. However, etretinate (ETR) showed no toxicity, suggesting maternal factors influence in vivo retinoid teratogenicity.

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    Area of Science:

    • Developmental toxicology
    • Pharmacology
    • Teratology

    Background:

    • Retinoids are crucial for embryonic development but can be teratogenic.
    • Understanding the in vitro vs. in vivo toxicity of retinoids is essential for risk assessment.

    Purpose of the Study:

    • To compare the developmental toxicity of various retinoids in an in vitro rat conceptus culture system.
    • To investigate the role of maternal pharmacokinetics and bioactivation in retinoid-induced teratogenicity.

    Main Methods:

    • Mid-gestation rat conceptuses were cultured for 48 hours.
    • Conceptuses were exposed to all-trans-retinoic acid (TRA), 13-cis-retinoic acid (13-CRA), etretinate (ETR), etretin, and six retinamides at varying concentrations.
    • Developmental abnormalities and toxicity were assessed.

    Main Results:

    • TRA was toxic at 0.5 µg/ml; 13-CRA and etretin caused abnormalities at 1.0 µg/ml.
    • Six retinamides were less toxic, with effects seen at 50-100 µg/ml.
    • ETR showed no toxicity even at 100 µg/ml, contrasting with its known in vivo teratogenicity.

    Conclusions:

    • In vitro results suggest maternal pharmacokinetics and bioactivation significantly influence in vivo retinoid teratogenicity.
    • Cis/trans isomerization is not a primary determinant of retinoid toxicity.
    • A correlation exists between abnormal development and the pKa values of tested retinoids.

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