Species dependent substrate specificity of the human and mouse OATP2B1/Oatp2b1

Abstract

Knockout mouse models are valuable tools to investigate the role of transporters in drug disposition and hepatotoxicity. However, due to limited understanding of species differences in substrate specificity, extrapolation of transporter data between species can be problematic. In vitro expression systems are a critical tool to screen for substrates and to delineate differences between human and mouse transporters. Therefore, the objective of the current study was to compare the substrate specificities of human OATP2B1 to mouse Oatp2b1. We used a CHO cell line stably expressing OATP2B1 and HEK293 cells transiently expressing Oatp2b1 and measured uptake of radiolabeled substrates. Our results confirm the model compounds estrone‐3‐sulfate and bromosulfophthalein as substrates for both the human and the mouse transporter. Additionally, we identified the anticancer drug paclitaxel and the anti‐HIV drug saquinavir as substrates for human OATP2B1. Mouse Oatp2b1 demonstrated a broader substrate specificity and transported numerous substrates including docetaxel, oleic acid, methotrexate, paclitaxel, ritonavir and saquinavir. Based on these data we conclude that the OATP2B sub‐family contains multispecific xenobiotic transporters with the mouse Oatp2b1 having a broader substrate specificity than its human ortholog.