Interactions of 1-methyl-4-phenylpyridinium and other compounds with P-glycoprotein: relevance to toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

The vesicular monoamine transporter 2 (VMAT2) has sequence homology with bacterial multidrug transporters which in turn share homology with mammalian P-glycoprotein (P-GP). Both VMAT2 and P-GP can detoxify cells. 1-Methyl-4-phenylpyridinium (MPP⁺), the toxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), is a substrate for VMAT2 that has several structural features in common with P-GP substrates and inhibitors. The present studies investigated whether P-GP is responsible for the elimination of MPP⁺ from the brain. Additionally, VMAT2 and P-GP are inhibited by many of the same compounds. Thus we also investigated whether VMAT2 inhibitors could block P-GP in vitro and vice versa whether P-GP inhibitors could block VMAT2 mediated transport of [³H]-DA into synaptic vesicles. In mice treated with MPTP and a P-GP inhibitor (quinidine, trans-flupentixol or cyclosporine A), the elimination of MPP⁺ from the striatum was significantly delayed. However, in experiments using various cell lines expressing either mouse or human P-GP, MPP⁺ did not reverse the P-GP mediated resistance to vincristine, suggesting that MPP⁺ is a poor substrate for P-GP. Additional experiments were performed using mdr1a/b double knockout mice which lack functional P-GP encoded by these two genes. Data from mdr1a/b knockout mice treated with MPTP also suggest that MPP⁺ is not extruded from the brain by P-GP. In other studies, we demonstrated that the VMAT2 inhibitors tetrabenazine and Ro 4-1284 inhibit P-GP and that the P-GP inhibitors trans-flupentixol and quinidine inhibit VMAT2. Thus, several new drugs can be added to the list of compounds that are able to inhibit both VMAT2 and P-GP, providing further evidence of the similarity between these two transporters.