Marked resistance of rar [gamma]-deficient mice to the toxic
effects of retinoic acid.
Look, Jutta, Jorg Landwehr, Franz Bauer, Anne Schmitt Hoffmann, Horst
Bluthmann, and Peter Lemotte.
Preclinical Research, Departments of Dermatology, Drug Metabolism
and Kinetics, and New Technologies, F. Hoffmann-LaRoche, CH-4002
Basel, Switzerland
APStracts 2:0038E, 1995.
Excessive intake of retinol or of retinoic acid causes a syndrome of
characteristic toxic effects known as hypervitaminosis A. To test the
role of the nuclear retinoic acid receptor RAR[gamma] in this process
we produced mice with a targeted disruption of the RAR[gamma] gene
and examined toxic effects of repeated doses of retinoic acid and two
other synthetic retinoids, Ro 15-1570 and Ro 40-6055. Surprisingly,
homozygous mutant mice were resistant to four-fold higher doses of
retinoic acid than wild type mice as well as elevated doses of the
synthetic retinoids, indicating that RAR[gamma] may have a major role
in mediating retinoid toxicity, a finding which possibly has
practical implications for reducing the toxicity of synthetic
retinoids in clinical use.
Received 22 August 1994; accepted in final form 16 February 1995.
APS Manuscript Number E340-4.
Article publication pending Am. J. Physiol. (Endocrinol. Metab.).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 1 March 1995.