MULTIDRUG-RESISTANCE PROTEIN-1 PROTECTS THE OROPHARYNGEAL MUCOSAL LAYER AND THE TESTICULAR TUBULES AGAINST DRUG-INDUCED DAMAGE

The multidrug resistance protein 1 (MRP1) gene encodes a transporter p rotein that helps to protect cells against xenobiotics. Elevated level s of MRP1 in tumor cells can result in active extrusion of a wide rang e of (anticancer) drugs with different cellular targets, a phenomenon called multidrug resistance (MDR). To explore the protective function of the mouse mrp1 protein during drug treatment, we investigated the t oxicity caused by the anticancer drug etoposide-phosphate (ETOPOPHOS) in mice lacking the mrp1 gene (mrp1(-/-) mice). We show here that the lack of mrp1 protein results in increased etoposide-induced damage to the mucosa of the oropharyngeal cavity and to the seminiferous tubules of the testis. The high concentrations of mrp1 that we find in the ba sal layers of the oropharyngeal mucosa and in the basal membrane of th e Sertoli cells in the testis apparently protect wild-type mice agains t this tissue damage. We also find drug-induced polyuria in mrp1(-/-) mice, which correlates with the presence of mrp1 protein in the urinar y collecting tubules, the major site of kidney water reabsorption. Our results indicate that specific inhibitors of MRP1 used to reverse MDR , in combination with carcinostatic drugs transported by MRP1, might l ead to drug-induced mucositis, (temporary) infertility, and diabetes i nsipidus.