The two human transporters OATP1B1 and OATP1B3 are crucial players in the process of drug uptake into hepatocytes which is an important aspect of hepatobiliary drug disposition. Both OATPs can transport many of the same common drugs and their function can be affected by other drugs or by interactions with other proteins, leading to potentially dangerous adverse drug interactions. In the previous grant periods, we have demonstrated that transport by OATP1B1 or OATP1B3 can be inhibited or stimulated depending on the transported substrate. However, the molecular mechanism of this substrate dependent modulation of uptake and the mechanism of modulation by protein interactions are not understood. Because both of these interactions can potentially lead to adverse drug effects and affect OATP-mediated drug disposition, their mechanism(s) of action need to be elucidated. Our long-term research goal is to understand in detail the mechanism of OATP-mediated transport as an essential prerequisite to understanding, predicting, and preventing OATP-related adverse drug-drug interactions. The objective of this application is to elucidate the mechanisms of how OATP1B1 and OATP1B3 function can be modulated in human hepatocytes. Our central hypothesis is that OATP-mediated transport is regulated by interacting proteins. The rationale for the proposed research is that understanding how OATP activity is regulated in the presence of interacting proteins may provide information to explain pathological observations, improve drug therapy, and prevent drug-drug interactions. Furthermore, the characterization of transporter-protein interactions will yield a more comprehensive understanding of the mechanisms of OATP transport. We plan to test the hypothesis with two specific aims: 1) Identify and characterize mechanisms of protein-protein interactions with OATP1B1 and OATP1B3; and 2) Characterize how the interacting proteins affect OATP1B-mediated transport; Completion of these specific aims will identify proteins that interact with human OATP1B family members, clarify to what extent such interactions affect OATP- mediated transport and thus drug disposition, and clarify physiological/pathophysiological aspects of OATP1B expression in human hepatocytes. This contribution is significant because its results will expand the fundamental understanding of the molecular mechanism of OATP-mediated transport and allow us to understand potential interactions not only at the drug-drug interaction level but also at the level of interacting proteins.
The proposed research is relevant to public health because a fundamental understanding of the interaction of OATP1B1 and OATP1B3 with other proteins as well as interactions with drugs and other chemicals will provide the essential information to predict OATP-mediated drug transport, ultimately leading to more effective and efficient therapies.
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