Aim. The human organic cation transporter subtype 2 (OCT2) is highly expressed in the renal tubular epithelium and can play an important role in the renal clearance of many drugs and drug-drug interactions occurring in the kidney. The purposes of this study are: (1) to investigate the genetic polymorphisms of OCT2 in Chinese population; (2) to evaluate the potential genotype-phenotype relationship involving OCT2 polymorphism in human subjects; and (3) to identify the SNPs in proximal promoter/enhancer region and assess their functional significance. / Conclusion. The present study demonstrated the existence of genetic polymorphisms of OCT2 gene in the Chinese population and for the first time showed that a ncSNP 808G>T is associated with a reduced renal transport function and can significantly impact the magnitude of drug interactions. Our study also for the first time found that a promoter polymorphism (-1283 T>C) is associated with an altered promoter activity in vitro, but no such relationship was observed with this SNP in the in vivo metformin study. Thus, it was the ncSNP 808G>T but not the -1283T>C in promoter that was associated with variations in the metformin renal clearance. (Abstract shortened by UMI.) / Method. One hundred and twelve Hong Kong Chinese subjects were recruited and their DNA samples were obtained. / Results. A total of 13 SNPs were identified in the coding and surrounding non-coding regions of OCT2, with minor allele frequencies (MAF) ranged from 4.5% to 24.7%. From these SNP data sets, 28 haplotypes were inferred with 4 being the common ones (frequencies ranged from 5.4% to 50.4%). Only one non-synonymous coding region SNP (ncSNP), 808G>T in the exon 4, was observed among all the identified SNPs. Significant differences were observed in the renal clearance of metformin in subjects with different mutation status for this variant. The mean renal tubular clearance (CLt) values of metformin were 8.54 +/- 1.86, 7.72 +/- 0.64, and 6 36 +/- 0.98 ml/kg/min for subjects with GG (n = 6), GT (n = 5) and TT (n = 4) genotypes respectively (P = .043. 1-way ANOVA). After a 6-day cimetidine treatment, a mean decrease of 50.7%, 34.6% and 18.9% in metformin CLt was observed in the GG, GT and TT genotype groups (P =.013, P =.002 and P = .065 respectively compared to metformin alone). The decrease of CLt was significantly lower in the TT genotype group than that in the GG group (P = .027). Five SNPs were identified and 5 haplotypes inferred (frequencies ranged from 2.7% to 38.4%) in promoter/enhancer area. One haplotype, characterized by the presence of -1283 T>C, was associated with a significantly lower luciferase activity in vitro (26.7% decrease in comparison to wild-type, P = .016), but not with metformin CLt in Chinese Subjects. / Wang, Zhijun. / "Aug 2007." / Adviser: Moses Chow. / Source: Dissertation Abstracts International, Volume: 69-02, Section: B, page: 0966. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (p. 148-168). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.
| Identifer | oai:union.ndltd.org:cuhk.edu.hk/oai:cuhk-dr:cuhk_344083 |
| Date | January 2007 |
| Contributors | Wang, Zhijun, Chinese University of Hong Kong Graduate School. Division of Pharmacy. |
| Source Sets | The Chinese University of Hong Kong |
| Language | English, Chinese |
| Detected Language | English |
| Type | Text, theses |
| Format | electronic resource, microform, microfiche, 1 online resource (xxv, 168 p. : ill.) |
| Rights | Use of this resource is governed by the terms and conditions of the Creative Commons “Attribution-NonCommercial-NoDerivatives 4.0 International” License (http://creativecommons.org/licenses/by-nc-nd/4.0/) |
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