Novel single nucleotide polymorphisms of organic cation transporter 1 (SLC22A1) affecting transport functions.
Organic cation transporter OCT1 (SLC22A1) plays an essential role in absorption, distribution, and excretion of various xenobiotics including therapeutically important drugs. In the present study, we analyzed the functional properties of the single nucleotide polymorphisms (SNPs) in SLC22A1 gene found in Japanese control individuals. Four mutations resulting in the amino acid changes (F160L, P283L, R287G, and P341L) were functionally characterized in Xenopus oocyte expression system. Two new SNPs, identified in Japanese population, P283L and R287G exhibited no uptake of both [14C]TEA and [3H]MPP+, although their protein expressions were detected in the plasma membrane of the oocytes injected with their cRNAs. Uptake of [14C]TEA by P341L was reduced to 65.1% compared to wild type, whereas F160L showed no significant change in its transport activity. This study suggests that the newly found OCT1 variants will contribute to inter-individual variations leading to the differences in cationic drug disposition and perhaps certain disease processes.
Sakata
Takeshi
T
Department of Pharmacology and Toxicology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo 181-8611, Japan.
Anzai
Naohiko
N
Shin
Ho Jung
HJ
Noshiro
Rie
R
Hirata
Taku
T
Yokoyama
Hirokazu
H
Kanai
Yoshikatsu
Y
Endou
Hitoshi
H
D000818:Animals; D001692:Biological Transport; D002412:Cations; D002462:Cell Membrane / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007564:Japan; D007700:Kinetics; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009865:Oocytes / Q000378:metabolism; D027702:Organic Cation Transporter 1 / Q000235:genetics*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D026902:Potassium Channel Blockers / Q000494:pharmacology; D018075:RNA, Complementary / Q000378:metabolism; D019789:Tetraethylammonium / Q000737:chemistry; D014981:Xenopus
D002412:Cations; D018076:DNA, Complementary; D027702:Organic Cation Transporter 1; D026902:Potassium Channel Blockers; D018075:RNA, Complementary; D019789:Tetraethylammonium