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Am J Physiol Endocrinol Metab 269: E91-E98, 1995;
0193-1849/95 $5.00
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AJP - Endocrinology and Metabolism, Vol 269, Issue 1 E91-E98, Copyright © 1995 by American Physiological Society

ARTICLES

Marked resistance of RAR gamma-deficient mice to the toxic effects of retinoic acid

J. Look, J. Landwehr, F. Bauer, A. S. Hoffmann, H. Bluethmann and P. LeMotte
Department of Dermatology, F. Hoffmann-LaRoche, Basel, Switzerland.

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 fourfold higher doses of retinoic acid than wild-type mice as well as to elevated doses of the synthetic retinoids, indicating that RAR gamma may have a major role in mediating retinoid toxicity, a finding that possibly has practical implications for reducing the toxicity of synthetic retinoids in clinical use.


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