Hepatic uptake transport proteins are now recognized as clinically relevant determinants of variable drug responsiveness and unexpected drug-drug interactions. Organic anion transporting polypeptides (OATP) 1B1 and OATP1B3 are liver-specific, and are major uptake transport proteins that mediate uptake, from blood into the liver, of a diverse array of endogenous compounds (e.g. bile acids), environmental toxins, and many clinically important drugs, including lipid-lowering statins, antibiotics, immunosuppressants, cardiac glycosides, antidiabetic and anticancer agents. Therefore, OATP proteins have significant relevance to human health. Dysfunction of OATP1B1 and OATP1B3 is closely related with altered drug pharmacokinetics and toxicity. Genetic polymorphisms of OATP1B1 and OATP1B3 that have decreased transport function are associated with markedly increased plasma concentrations/systemic exposure of many substrates (e.g., statins, irinotecan, digoxin). The c. 512T>C (V174A) variant of OATP1B1 is the most robust and important predictor of statin-induced myopathy. The long-term goal of this research program is to define the molecular mechanism(s) that affect drug/toxin disposition through OATP1B1 and OATP1B3, and to predict and prevent OATP-mediated drug-drug interactions in humans. To date, only scattered information is known regarding mechanisms involved in regulating OATP1B1 and OATP1B3 function, most of which were studied at the transcriptional level. The objectives of this application are to elucidate the potential role of posttranslational regulation, via phosphorylation and the ubiquitin system, in modulating OATP1B1 and OATP1B3 function. The proposed studies are based on my preliminary results that: 1) OATP1B3 is a phosphorylated protein and the function of OATP1B1 and OATP1B3 is regulated by protein kinase C activation;2) the ubiquitin system is involved in OATP1B1 and OATP1B3 degradation, and proteasome inhibition affects OATP1B1 and OATP1B3 function.
The specific aims are as follows:
Aim 1. Elucidate the impact of altered phosphorylation status on OATP1B1 and OATP1B3 transport function and membrane localization.
Aim 2. Define the regulation of OATP1B1 and OATP1B3 degradation and trafficking by the ubiquitin system. The proposed research is innovative and relevant to human health because an understanding of the mechanism(s) that are involved in regulating OATP1B1 and OATP1B3 function is essential to predict potential drug-drug interactions, and provide helpful information in drug development to prevent OATP-mediated drug- drug interactions. The outcomes of these experiments will greatly broaden our ability to predict and prevent transport-mediated drug-drug interactions.

Public Health Relevance

Organic anion transporting polypeptides (OATP1B1 and OATP1B3) mediate the uptake of many drugs and endogenous compounds from blood into the liver. The proposed research will elucidate altered regulatory mechanisms that modulate the function of these important liver-specific proteins. Such information is essential to predict clinically relevant drug-drug and drug-disease interactions.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01GM094268-05
Application #
8716772
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Okita, Richard T
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Oklahoma Health Sciences Center
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
City
Oklahoma City
State
OK
Country
United States
Zip Code
73117