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1 Department of Physiology, Mahidol University, Bangkok, Bangkok, Thailand; Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, New York, United States
2 Pharmacology, SUNY Upstate Medical University, Syracuse, New York, United States
3 Department of Physiology, Mahidol University, Bangkok, Bangkok, Thailand
4 United States; Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, New York, United States
* To whom correspondence should be addressed. E-mail: ned_ballatori{at}urmc.rochester.edu.
The organic anion transporting polypeptides (OATP/SLCO) are generally believed to function as electroneutral anion exchangers, but direct evidence for this contention has only been provided for one member of this large family of genes, rat Oatp1a1/Oatp1 (Slco1a1). In contrast, a recent study indicates that human OATP1B3/OATP-8 (SLCO1B3) functions as a GSH-bile acid co-transporter. The present study examined the transport mechanism and possible GSH requirement of the two members of this protein family that are expressed in relatively high levels in human liver, OATP1B3/OATP-8 and OATP1B1/OATP-C (SLCO1B1). Uptake of taurocholate in Xenopus laevis oocytes expressing either OATP1B1/OATP-C, OATP1B3/OATP-8, or polymorphic forms of OATP1B3/OATP-8, namely S112A and/or M233I was cis-inhibited by taurocholate and estrone sulfate, but was unaffected by GSH. Likewise, taurocholate and estrone sulfate transport were trans-stimulated by estrone sulfate and taurocholate, but was unaffected by GSH. OATP1B3/OATP-8 also did not mediate GSH efflux or GSH-taurocholate cotransport out of cells, indicating that GSH is not required for transport activity. In addition, estrone sulfate uptake in oocytes microinjected with OATP1B3/OATP-8 or OATP1B1/OATP-C cRNA was unaffected by depolarization of the membrane potential or by changes in the pH, suggesting an electroneutral transport mechanism. Overall, these results indicate that OATP1B3/OATP-8 and OATP1B1/OATP-C most likely function as bidirectional facilitated diffusion transporters, and that GSH is not a substrate or activator of their transport activity.
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