title: Genetic variants of organic cation transporter 1 (OCT1) and OCT2 significantly reduce lamivudine uptake.
abstract: The study sought to investigate the effect of genetic variants of OCT1 (OCT1-P283L and -P341L) and OCT2 (OCT2-T199I, -T201M and -A270S), which were identified in a Korean population, on the transport of lamivudine in vitro and to compare the substrate dependent effects of OCT1 and OCT2 variants with 1-methyl-4-phenylpyridinium (MPP+), tetraethyl ammonium (TEA), metformin and lamivudine as substrates for these transporters. When the transport kinetics of lamivudine uptake in oocytes overexpressing OCT1 and OCT2 wild-type (WT) and variant proteins were measured, lamivudine uptake mediated by OCT1-WT was saturable, and uptake was decreased in oocytes expressing OCT1-P283L and -P341L variants compared with that in OCT1-WT. The Clint of lamivudine in oocytes expressing OCT1-P283L was decreased by 85.1% compared with OCT1-WT, whereas it was decreased by 48.7% in oocytes expressing OCT1-P341L. The Clint of lamivudine in oocytes expressing OCT2-T199I, -T201M and -A270S was decreased by 86.2%, 88.9% and 73.6%, respectively, compared with OCT2-WT. When comparing various substrates such as MPP+, TEA, metformin and lamivudine, the effects of the OCT1 genetic polymorphisms on their uptake were not identical. However, contrary to the case of OCT1, the uptake of MPP+, TEA, metformin and lamivudine in oocytes expressing OCT2-T199I, -T201M and -A270S variants was decreased significantly compared with that in oocytes expressing OCT2-WT. In conclusion, the effect of genetic variations of OCT1 and OCT2 on the uptake of MPP+, TEA, metformin and lamivudine was substrate-dependent.
authors.affiliation: College of Pharmacy, Dankook University, Cheon-an, 330-714, Korea.
authors.forename: Min-Koo
authors.initials: MK
authors.lastname: Choi
authors.forename: Im-Sook
authors.initials: IS
authors.lastname: Song
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism; D019943:Amino Acid Substitution; D044466:Asian People / Q000235:genetics; D006801:Humans; D019259:Lamivudine / Q000378:metabolism*; D008687:Metformin / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D027702:Organic Cation Transporter 1 / Q000235:genetics* / Q000378:metabolism; D000075102:Organic Cation Transporter 2; D020641:Polymorphism, Single Nucleotide; D019789:Tetraethylammonium / Q000378:metabolism
chemical_list: D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1; D000075102:Organic Cation Transporter 2; C491013:SLC22A2 protein, human; D019259:Lamivudine; D019789:Tetraethylammonium; D008687:Metformin; D015655:1-Methyl-4-phenylpyridinium