Received for publication July 12, 2004.
Revised December 30, 2004.
Accepted for publication January 3, 2005.

Molecular Determinants of Substrate/Inhibitor Binding to the Human and Rabbit Renal Organic Cation Transporters, hOCT2 and rbOCT2

Abstract

Organic cation transporters are important for the elimination of many drugs and toxins from the body. In the present study, substrate-transporter interactions were investigated in CHO cells stably transfected with either the human or rabbit orthologs of the principal organic cation transporter in the kidney, OCT2. IC₅₀ values, ranging from 0.04 µM to > 3 mM, for inhibition of [¹⁴C]TEA transport were determined for more than 30 structurally diverse compounds. Although the two OCT orthologs displayed similar IC₅₀ values for some of these compounds, the majority varied by as much as 20-fold. Marked differences in substrate affinity were also noted when comparing hOCT2 to the closely related homolog, hOCT1. These data suggest the molecular determinants of substrate binding differ markedly among both homologous and orthologous OCT transporters. The software package Cerius² (Accelrys, San Diego, CA) was used to generate a descriptor-based 2D-quantitative structure activity relationship (QSAR) to produce a model relating the affinity of hOCT2 to particular physicochemical features of substrate/inhibitor molecules (r² = 0.81). Comparative molecular field analysis (CoMFA; Tripos, St Louis, MO) was used to generate 3D-QSARs describing the structural basis of substrate binding to hOCT2 and rbOCT2 (q² = 0.60 and 0.53, respectively, and each with r² = 0.97). The quality of the models was assessed by their ability to successfully predict the inhibition of a set of test compounds. The current models enabled prediction of OCT2 affinity and may prove useful in the prediction of unwanted drug interactions at the level of the renal secretory process.

Key words: Biogenic Amine, Structure-activity relationships and modeling, Liver transporters, Structure/function/mechanism