Characterization of the efflux of the organic cation MPP+ in cultured rat hepatocytes.
The aim of this study was to characterize the efflux of organic cations from primary cultured rat hepatocytes, using 1-methyl-4-phenylpyridinium (MPP+) as a model compound. The efflux of [3H]MPP+ was temperature dependent, and pH and metabolic inhibition independent. It was either strongly reduced (verapamil, vinblastine and rhodamine123) or only moderately reduced (daunomycin) by other organic cations. The anti-P-glycoprotein antibody UIC2 (20 microg/ml) and the P-glycoprotein inhibitors vanadate and cyclosporine A had no effect on [3H]MPP+ efflux. Decynium22 and corticosterone, known inhibitors of rat Organic Cation Transporter 1 (rOCT1), markedly reduced [3H]MPP+ efflux. The uptake of [3H]MPP+ into hepatocytes, known to be mediated by rOCT1, was inhibited by verapamil and vinblastine (IC50s of 2.6 and 34.4 microM, respectively). In conclusion, [3H]MPP+ efflux from primary cultured rat hepatocytes appears to be mediated by rOCT1, a polyspecific organic cation transporter. Moreover, our results do not support the involvement of P-glycoprotein or of an organic cation/proton antiporter in the efflux of [3H]MPP+.
Martel
F
F
Department of Biochemistry, Faculty of Medicine, Porto, Portugal.
Ribeiro
L
L
Calhau
C
C
Azevedo
I
I
D015655:1-Methyl-4-phenylpyridinium / Q000493:pharmacokinetics*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D015259:Dopamine Agents / Q000493:pharmacokinetics*; D016623:Ion Pumps / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D027702:Organic Cation Transporter 1; D051381:Rats; D017208:Rats, Wistar
D002352:Carrier Proteins; D015259:Dopamine Agents; D016623:Ion Pumps; D008565:Membrane Proteins; D027702:Organic Cation Transporter 1; D015655:1-Methyl-4-phenylpyridinium