Cmdr1, a chicken P-glycoprotein, confers multidrug resistance and interacts with estradiol

We have cloned from a chicken intestinal cDNA library Cmdr1, the first avia n P-glycoprotein. Cmdr1 is 67% and 69% identical to proteins encoded by the human MDR1 and MDR2 genes, respectively. Functional expression of Cmdr1 in both mouse NIH 3T3 and yeast cells demonstrated that Cmdr1 represents the avian ortholog of human Mdr1, since it confers resistance to several antica ncer drugs and the fluorescent dye rhodamine 6G. Northern and immunoblot an alysis showed that CMDR1 is highly expressed throughout the intestine and i n the liver, and to a considerable extent in kidney, brain, lung, heart, ey e and follicles, In situ hybridization revealed a cell type-specific expres sion of CMDR1 in the intestinal epithelium, with high levels in the villi o f the small and large intestine as well as crypt cells. These data suggest that Cmdr1 could play a role in intestinal detoxification. Most interesting ly, immunoblotting showed that Cmdr1 is also expressed in ovarian tissues, particularly in theca cells, the major site for ovarian estrogen production in birds. Indeed, competition experiments indicated that Cmdr1 interacts w ith estradiol, since rhodamine 6G efflux was efficiently blocked by estradi ol in NIH 3T3 cells expressing Cmdr1, Rhodamine efflux was also blocked by PSC-833, a specific inhibitor of steroid-transporting P-glycoproteins from mammalian cells. We propose that Cmdr1 in ovarian cells could be involved i n the cell type-specific transport or release of estrogen that is essential for avian follicular development.