Organic cation transporters in the kidney play key roles in the body's defense against foreign substances including drugs and other xenobiotics. Many clinically used drugs (e.g., metformin ), hormones (e.g., dopamine) as well as toxic substances (e.g., MPP+ (1-methyl-4-phenylpyridinium)) are organic amines and are eliminated in the kidney by secretory transporters. The working hypothesis of the proposed studies is that the organic cation transporter, OCT2, is localized to the basolateral membrane of the proximal tubule and is the key transporter responsible for the first step in the renal secretion of many organic cations. To test this hypothesis, comprehensive studies, ranging from molecular analysis of specificity through studies of an OCT2 knockout mouse and genetic studies in humans, are proposed.
The specific aims are to: (1) Determine the specificity of OCT2 in heterologous expression systems; (2) Construct a humanized cell culture model to localize the transporter to the apical or basolateral membrane and localize the transporter along the nephron; (3) Determine the role of OCT2 in renal secretion by studying renal elimination and accumulation in an OCT2 knockout mouse that will be provided by our collaborator, A. Schinkel; and (4) Determine whether genetic variation in OCT2 contributes to variation in renal clearance of the model organic cation, metformin, an anti-diabetic drug, in humans. Methods used in analysis of specificity of OCT2 include two-electrode voltage clamp methods in oocytes. Confocal microscopy, in situ hybridization techniques and immunohistochemistry will be used to localize OCT2 to the apical or basolateral membrane and to ascertain the regional specific distribution of the transporter along the nephron. Pharmacokinetic studies in mice will be used to determine the role of the transporter in in vivo renal elimination. Finally, clinical studies in normal volunteers with particular OCT2 genotypes and haplotypes including OCT2*1, OCT*3D and three missense mutations (M1651, R400C, K432Q) will be performed to determine whether genetic variation in OCT2 contributes to variation in renal clearance of metformin. These variants have been shown in cells to have altered function in comparison to the common form of OCT2. These studies are significant to our basic understanding of the mechanisms involved in renal drug elimination and will enhance our ability to predict renal clearance, toxicities and drug response.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM036780-18
Application #
6851663
Study Section
Pharmacology A Study Section (PHRA)
Program Officer
Long, Rochelle M
Project Start
1986-04-04
Project End
2007-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
18
Fiscal Year
2005
Total Cost
$330,994
Indirect Cost
Name
University of California San Francisco
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Chen, Ligong; Shu, Yan; Liang, Xiaomin et al. (2014) OCT1 is a high-capacity thiamine transporter that regulates hepatic steatosis and is a target of metformin. Proc Natl Acad Sci U S A 111:9983-8
Yee, Sook Wah; Chen, Ligong; Giacomini, Kathleen M (2012) The role of ATM in response to metformin treatment and activation of AMPK. Nat Genet 44:359-60
Minematsu, Tsuyoshi; Giacomini, Kathleen M (2011) Interactions of tyrosine kinase inhibitors with organic cation transporters and multidrug and toxic compound extrusion proteins. Mol Cancer Ther 10:531-9
Li, Shuanglian; Chen, Ying; Zhang, Shuzhong et al. (2011) Role of organic cation transporter 1, OCT1 in the pharmacokinetics and toxicity of cis-diammine(pyridine)chloroplatinum(II) and oxaliplatin in mice. Pharm Res 28:610-25
Choi, J H; Yee, S W; Ramirez, A H et al. (2011) A common 5'-UTR variant in MATE2-K is associated with poor response to metformin. Clin Pharmacol Ther 90:674-84
More, Swati S; Itsara, Melissa; Yang, Xiaodong et al. (2011) Vorinostat increases expression of functional norepinephrine transporter in neuroblastoma in vitro and in vivo model systems. Clin Cancer Res 17:2339-49
Kido, Yasuto; Matsson, Pär; Giacomini, Kathleen M (2011) Profiling of a prescription drug library for potential renal drug-drug interactions mediated by the organic cation transporter 2. J Med Chem 54:4548-58
More, Swati S; Akil, Omar; Ianculescu, Alexandra G et al. (2010) Role of the copper transporter, CTR1, in platinum-induced ototoxicity. J Neurosci 30:9500-9
Ianculescu, Alexandra G; Friesema, Edith C H; Visser, Theo J et al. (2010) Transport of thyroid hormones is selectively inhibited by 3-iodothyronamine. Mol Biosyst 6:1403-10
Chen, Ligong; Takizawa, Miho; Chen, Eugene et al. (2010) Genetic polymorphisms in organic cation transporter 1 (OCT1) in Chinese and Japanese populations exhibit altered function. J Pharmacol Exp Ther 335:42-50

Showing the most recent 10 out of 70 publications