Journal Article

Fluorothalidomide: A Characterization of Maternal and Developmental Toxicity in Rabbits and Mice

Crystal J. J. Lee, Norio Shibata, Michael J. Wiley and Peter G. Wells

in Toxicological Sciences

Volume 122, issue 1, pages 157-169
Published in print July 2011 | ISSN: 1096-6080
Published online April 2011 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfr086
Fluorothalidomide: A Characterization of Maternal and Developmental Toxicity in Rabbits and Mice

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The expanding therapeutic uses of thalidomide (TD) are limited by its teratogenic side effects. Although the therapeutic and teratogenic effects may be stereoselectively separable, rapid in vivo racemization of the TD isomers confounds the corroboration of this distinction. Herein we evaluated the potential of fluorothalidomide (FTD), the closest structural analog of TD with stable, nonracemizing isomers, as a model compound for studying stereoselectivity in TD teratogenesis. In contrast to TD, FTD was a potent maternal and fetal toxicant in both rabbits and mice in vivo. Furthermore, FTD rapidly degraded in vivo, presumably via hydrolysis, which in vitro was up to 22-fold faster for FTD than TD. Most critically, in an established rabbit embryo culture model for TD teratogenesis, FTD did not initiate the limb bud embryopathies observed with TD. The chemical instability and strikingly different maternal and developmental toxicological profiles of FTD and TD make FTD an unsuitable compound for studying stereoselective mechanisms of TD teratogenesis.

Keywords: thalidomide; hydrolysis; fluorinated analog; teratogenesis; embryopathies

Journal Article.  7940 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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