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Novel single nucleotide polymorphisms of organic cation transporter 1 (SLC22A1) affecting transport functions

Takeshi Sakata1, Naohiko Anzai, Ho Jung Shin

  • 1Department of Pharmacology and Toxicology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo 181-8611, Japan.

Biochemical and Biophysical Research Communications
|December 31, 2003
PubMed

Insights

Single nucleotide polymorphisms (SNPs) in the organic cation transporter OCT1 (SLC22A1) gene impact drug metabolism. Newly identified Japanese OCT1 variants, P283L and R287G, show no drug uptake, affecting drug disposition.

Area of Science:

  • Pharmacogenomics
  • Molecular Biology
  • Drug Metabolism

Background:

  • The organic cation transporter 1 (OCT1), encoded by the SLC22A1 gene, is crucial for the absorption, distribution, and excretion of numerous xenobiotics, including vital medications.
  • Genetic variations, specifically single nucleotide polymorphisms (SNPs), can alter transporter function, leading to significant inter-individual differences in drug response and efficacy.

Purpose of the Study:

  • To investigate the functional impact of SLC22A1 gene single nucleotide polymorphisms (SNPs) identified in a Japanese population on the transport activity of organic cation transporter 1 (OCT1).
  • To characterize novel OCT1 variants and their potential contribution to variations in drug disposition and disease susceptibility.

Main Methods:

  • Functional characterization of four OCT1 variants (F160L, P283L, R287G, P341L) using a Xenopus oocyte expression system.
  • Assessment of transporter activity by measuring the uptake of radiolabeled substrates [14C]TEA and [3H]MPP+.
  • Confirmation of protein expression at the plasma membrane via cRNA injection in oocytes.

Main Results:

  • Two novel Japanese OCT1 variants, P283L and R287G, demonstrated a complete loss of transport function for both [14C]TEA and [3H]MPP+, despite detectable plasma membrane protein expression.
  • The P341L variant exhibited reduced [14C]TEA uptake (65.1% of wild-type activity), while the F160L variant showed no significant alteration in transport activity compared to the wild-type OCT1.
  • These findings highlight the functional consequences of specific OCT1 genetic variants on substrate transport.

Conclusions:

  • The newly identified OCT1 variants, particularly P283L and R287G, significantly impair transporter function, potentially leading to altered pharmacokinetics of OCT1-substrated drugs.
  • These genetic variations in OCT1 may contribute to inter-individual variability in drug disposition, influencing therapeutic outcomes and potentially disease risk.
  • Further research into OCT1 variants is essential for personalized medicine and predicting drug responses.

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