OATPOatp Isoform Mediated Transport

The mechanism driving OATP/Oatp-mediated transport has been investigated for several isoforms. OATP/Oatp members mediate the transport of organic anions and other compounds in a Na+-independent manner (Hagenbuch and Meier, 2003; Tirona and Kim, 2002; van Montfoort et al., 2003). Bidirectional transmembrane transport of BSP was observed in rat Oatp1 transfected cells (Shi et al., 1995), as well as rat Oatp1 mediated taurocholate/HCO3 exchange (Satlin et al., 1997) suggesting an anion exchange mechanism. Evidence implicates a role of glutathione (GSH) in rat Oatp1 and Oatp2 (Li et al., 1998, 2000) substrate transport. Li et al. (1998) demonstrated that rat Oatp1 mediated uptake of taurocholate and leukotriene C4 (LTC4) was significantly inhibited by high extracellular GSH concentrations, yet stimulated by high intracellular GSH. Additionally, GSH efflux across rat Oatp1 expressing oocytes was increased and further enhanced in the presence of extracellular Oatp1 substrates taurocholate or BSP (Li et al., 1998). Increased GSH efflux in Oatp2 expressing Xenopus oocytes was similarly observed (Li et al., 2000). Oatp2 mediated taurocholate transport was upregulated by high intracellular GSH, although changes of the extracellular GSH concentration had no effect (Li et al., 2000). Therefore, physiological GSH efflux down its electrochemical gradient could be an important driving force for rat Oatp1 and Oatp2 mediated transport.

A proton-coupled transport mechanism has also been suggested for OATP/Oatp isoforms (Kobayashi et al., 2003) based on the uptake of estrone-3-sulfate and pravastatin in OATP-B-transfected HEK 293 cells. It was demonstrated that uptake of both compounds were pH-dependent, with higher uptake at pH 5.5 in contrast to pH 7.4 (Kobayashi et al., 2003). Moreover, an increase in Vmax was observed with decrease of pH from 7.4 to 5.0, whereas the change in Km was negligible (Nozawa et al., 2004). This is analogous to the proton-dependent mechanism of uptake observed with POT family members discussed above. Additional work is required to identify the mechanism(s) by which each OATP/Oatp isoform mediates substrate uptake.

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