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 ba cterial multidrug transporters which in turn share homology with mammalian P-glycoprotein (P-GP). Both VMAT2 and P-GP can detoxify cells. 1-Methyl-4-p henylpyridinium (MPP+), the toxic metabolite of 1-methyl-4-phenyl-1,2,3,6-t etrahydropyridine (MPTP), is a substrate for VMAT2 that has several structu ral features in common with P-GP substrates and inhibitors. The present stu dies investigated whether P-GP is responsible for the elimination of MPP+ f rom the brain. Additionally, VMAT2 and P-GP are inhibited by many of the sa me compounds. Thus we also investigated whether VMAT2 inhibitors could bloc k P-GP in vitro and vice versa whether P-GP inhibitors could block VMAT2 me diated transport of [H-3]-DA into synaptic vesicles. In mice treated with M PTP and a P-GP inhibitor (quinidine, traps-flupentixol or cyclosporine A), the elimination of MPP+ from the striatum was significantly delayed. Howeve r, in experiments using various cell lines expressing either mouse or human P-GP, MPP+ did not reverse the P-GP mediated resistance to vincristine, su ggesting that MPP+ is a poor substrate for P-GP. Additional experiments wer e performed using mdr1a/b double knockout mice which lack functional P-GP e ncoded by these two genes. Data from mdr1a/b knockout mice treated with MPT P also suggest that MPP+ is not extruded from the brain by P-GP. In other s tudies, we demonstrated that the VMAT2 inhibitors tetrabenazine and Ro 4-12 84 inhibit P-GP and that the P-GP inhibitors traps-flupentixol and quinidin e inhibit VMAT2. Thus, several new drugs can be added to the list of compou nds that are able to inhibit both VMAT2 and P-GP, providing further evidenc e of the similarity between these two transporters. (C) 2001 Elsevier Scien ce B.V. All rights reserved.