Marked resistance of RAR gamma-deficient mice to the toxic effects of retinoic acid.
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.
Look
J
J
Department of Dermatology, F. Hoffmann-LaRoche, Basel, Switzerland.
Landwehr
J
J
Bauer
F
F
Hoffmann
A S
AS
Bluethmann
H
H
LeMotte
P
P
D000818:Animals; D001483:Base Sequence; D001565:Benzoates / Q000633:toxicity; D004351:Drug Resistance / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D015335:Molecular Probes / Q000235:genetics; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D012176:Retinoids / Q000633:toxicity; D012867:Skin / Q000187:drug effects; D013764:Tetrahydronaphthalenes / Q000633:toxicity; D014212:Tretinoin / Q000097:blood / Q000633:toxicity*; D000097768:Retinoic Acid Receptor gamma
D001565:Benzoates; D015335:Molecular Probes; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D013764:Tetrahydronaphthalenes; D014212:Tretinoin; D000097768:Retinoic Acid Receptor gamma; C068073:Am 580; C045042:Ro 15-1570