Roulet Alain, Puel Olivier, Gesta Stéphane, Lepage Jean-François, Drag Marlene, Soll Mark, Alvinerie Michel, Pineau Thierry
Laboratoire de Pharmacologie et Toxicologie, INRA-180 Chemin de Tournefeuille, BP 3, 31931 Toulouse Cedex 9, France.
Eur J Pharmacol. 2003 Jan 24;460(2-3):85-91. doi: 10.1016/s0014-2999(02)02955-2.
Multidrug resistance (MDR) phenotypes in cancer cells are associated with overexpression of the drug carrier P-glycoprotein. The antiparasitic drug ivermectin, one of its substrates, abnormally accumulates in the brain of transgenic mice lacking the P-glycoprotein, resulting in neurotoxicity. Similarly, an enhanced sensitivity to ivermectin has been reported in certain dogs of the Collie breed. To explore the basis of this phenotype, we analyzed the canine P-glycoprotein-encoding MDR1 gene, and we report the first characterization of the cDNA for wild-type (Beagle) P-glycoprotein. The corresponding transcripts from ivermectin-sensitive Collies revealed a homozygous 4-bp exonic deletion. We established, by genetic testings, that the MDR1 frame shift is predictable. Accordingly, no P-glycoprotein was detected in the homozygote-deficient dogs. In conclusion, we characterized a unique case of naturally occurring gene invalidation. This provides a putative novel model that remains to be exploited in the field of human therapeutics and that might significantly affect tissue distribution and drug bioavailability studies.
癌细胞中的多药耐药（MDR）表型与药物载体P-糖蛋白的过表达相关。抗寄生虫药物伊维菌素是P-糖蛋白的底物之一，在缺乏P-糖蛋白的转基因小鼠脑中异常蓄积，导致神经毒性。同样，在某些柯利犬中也报道了对伊维菌素的敏感性增强。为了探究这种表型的基础，我们分析了犬类编码P-糖蛋白的MDR1基因，并报道了野生型（比格犬）P-糖蛋白cDNA的首次特征描述。来自对伊维菌素敏感的柯利犬的相应转录本显示纯合子外显子4bp缺失。通过基因检测我们确定，MDR1移码是可预测的。因此，在纯合子缺陷犬中未检测到P-糖蛋白。总之，我们描述了一个自然发生的基因无效的独特案例。这提供了一个有待在人类治疗领域开发的假定新模型，可能会显著影响组织分布和药物生物利用度研究。
