Aims: Cadmium (Cd) damages the kidney by apoptosis, but chronic Cd exposure also leads to cancer. Previously, we showed Cd apoptosis is mediated by ceramide (Cer)-calpain signaling (Lee et al. 2007), but Cd also induced upregulation of the multidrug resistance transporter P-glycoprotein (MDR1) to promote kidney proximal tubule cell (PTC) survival (Thévenod et al. 2000). The aim of the study was to investigate mechanisms for MDR1 dependent survival of Cd exposed cells. Methods: Cytotoxicity was evaluated by MTT assay, H-33342 nuclear staining and electrical measurements (ECIS, Applied Biophysics, USA) in MDR1 overexpressing kidney cells (MDR1-MDCK) or PTC. Cer levels were determined by a diacylglycerol kinase assay and Cd efflux by ¹⁰⁹Cd measurements. Transfection was performed using Lipofectamine 2000 (Invitrogen, Germany). Results: Toxicity of 10-20 mM Cd and 10-50 mM C₆ Cer was significantly reduced by up to 75% and 60%, respectively, which was abolished by the MDR1 blocker PSC833. ECIS of MDCK and MDR1-MDCK monolayers ± Cd showed similar effects. Efflux of ¹⁰⁹Cd was not enhanced in MDR1-MDCK and was unaffected by MDR1 inhibitors (PSC833, C219). Lower basal total Cer levels were observed in MDR1-MDCK (0.31 ± 0.04 mM) compared to controls (0.49 ± 0.07 mM), which were increased by 67.2 ± 16.0% in MDCK but only by 21.9 ± 4.8% in MDR1-MDCK after 3 h Cd. Furthermore, induction of MDR1 expression in PTC by Wnt signalling (transfection of b-catenin and TCF4) reduced Cd-induced cell death by ~50%. Conclusions: Rather than exporting Cd, MDR1 seems to confer its protective effects against Cd-induced cell death by either reducing cellular Cer levels or by efflux of Cer metabolites. Funded by DFG TH 345/10-1 and TH 345/11-1. Lee, W.K., Torchalski, B. & Thevenod, F. 2007. Am J Physiol Cell Physiol 293, 839-847. Thevenod, F., Friedmann, J.M., Katsen, A.D. & Hauser I.A. 2000. J Biol Chem 275, 1887-1896.