Look J, Landwehr J, Bauer F, Hoffmann A S, Bluethmann H, LeMotte P
Department of Dermatology, F. Hoffmann-LaRoche, Basel, Switzerland.
Am J Physiol. 1995 Jul;269(1 Pt 1):E91-8. doi: 10.1152/ajpendo.1995.269.1.E91.
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.
视黄醇或视黄酸摄入过量会引发一种具有特征性毒性作用的综合征，称为维生素A过多症。为了测试核视黄酸受体（RARγ）在此过程中的作用，我们培育出了RARγ基因靶向敲除的小鼠，并研究了重复给予视黄酸以及另外两种合成类视黄醇Ro 15 - 1570和Ro 40 - 6055的毒性作用。令人惊讶的是，纯合突变小鼠对四倍于野生型小鼠剂量的视黄酸以及更高剂量的合成类视黄醇具有抗性，这表明RARγ可能在介导类视黄醇毒性方面起主要作用，这一发现可能对降低合成类视黄醇在临床应用中的毒性具有实际意义。
