Arnhold Thomas, Elmazar Mohamed M A, Nau Heinz
Zentrumsabteilung für Lebensmitteltoxikologie, Zentrum für Lebensmittelwissenschaften, Tierärztliche Hochschule Hannover, Bischofsholer Damm 15, D-30173 Hannover, Germany.
Toxicol Sci. 2002 Apr;66(2):274-82. doi: 10.1093/toxsci/66.2.274.
Previous studies in our laboratory showed a synergistic interaction of synthetic ligands selective for the retinoid receptors RAR and RXR in regard to teratogenic effects produced in mice (M. M. Elmazar et al., 2001, TOXICOL: Appl. Pharmacol. 170, 2-9). In the present study the influence of phytol and phytanic acid (a RXR-selective ligand) on the teratogenicity of retinol and the RAR-selective ligand all-trans-retinoic acid was investigated by coadministration experiments on day 8.25 of gestation in NMRI mice. Phytol and phytanic acid, noneffective when administered alone, did not potentiate the teratogenicity induced by retinol or all-trans-retinoic acid. On the contrary, phytol and phytanic acid greatly reduced retinol-induced teratogenic effects (ear anotia, tail defects, exencephaly). The effect of phytol on all-trans-retinoic acid teratogenesis was limited (only resorptions and tail defects were reduced). Pharmacokinetic studies in nonpregnant animals revealed that phytol coadministration with retinol reduced plasma levels of retinol and retinyl esters, and drastically reduced the levels of the teratogenic retinol metabolite, all-trans-retinoic acid. Phytanic acid also reduced the oxidative metabolism and teratogenic effects of retinol. These results indicate that phytol and phytanic acid did not synergize with retinol and all-trans-retinoic acid in our mouse teratogenesis model. Instead, phytol and phytanic acid effectively blocked the teratogenic effects of retinol by drastically reducing the metabolic production of all-trans-retinoic acid. Phytol and phytanic acid may be useful for the prevention of vitamin A teratogenicity.
我们实验室之前的研究表明，对维甲酸受体RAR和RXR具有选择性的合成配体在对小鼠产生致畸作用方面存在协同相互作用（M. M. 埃尔马扎尔等人，2001年，《毒理学：应用药理学》第170卷，第2 - 9页）。在本研究中，通过在NMRI小鼠妊娠第8.25天进行联合给药实验，研究了叶绿醇和植烷酸（一种RXR选择性配体）对视黄醇致畸性以及RAR选择性配体全反式维甲酸致畸性的影响。叶绿醇和植烷酸单独给药时无作用，并未增强视黄醇或全反式维甲酸诱导的致畸性。相反，叶绿醇和植烷酸极大地降低了视黄醇诱导的致畸作用（耳缺如、尾部缺陷、无脑畸形）。叶绿醇对全反式维甲酸致畸作用的影响有限（仅减少了吸收和尾部缺陷）。对非妊娠动物的药代动力学研究表明，叶绿醇与视黄醇联合给药可降低视黄醇和视黄酯的血浆水平，并大幅降低致畸性视黄醇代谢物全反式维甲酸的水平。植烷酸也降低了视黄醇的氧化代谢和致畸作用。这些结果表明，在我们的小鼠致畸模型中，叶绿醇和植烷酸与视黄醇和全反式维甲酸不存在协同作用。相反，叶绿醇和植烷酸通过大幅减少全反式维甲酸的代谢产生，有效地阻断了视黄醇的致畸作用。叶绿醇和植烷酸可能有助于预防维生素A致畸性。
