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Identification of genetic variations of the human organic cation transporter hOCT1 and their functional consequences
Abstract
By systematic mutation screening of the polyspecific organic cation transporter hOCT1 (SLC22A1) in 57 Caucasians, 25 genetic variations were identified and further analysed for population frequency. Five mutations resulting in the amino acid changes Arg61Cys, Cys88Arg, Phe160Leu, Gly401Ser, and Met420del, with respective allele frequencies of 9.1, 0.6, 22, 3.2, and 16%, were functionally characterized upon expression in Xenopus oocytes. Phe160Leu and Met420del exhibited substrate affinities and selectivites identical to hOCT1 wild-type. In contrast, uptake of 0.1 microm [3H]1-methyl-4-phenylpyridinium ([3H]MPP) by Arg61Cys, Cys88Arg and Gly401Ser were reduced to 30, 1.4 and 0.9% compared to wild-type, respectively. Since transport of 1 microm [3H]serotonin by Cys88Arg and Gly401Ser was reduced to only 13 and 12% of wild-type, these mutants exhibit a changed substrate selectivity. The data show that the mutants Arg61Cys, Cys88Arg and Gly401Ser could affect the disposition of OCT1 substrates and as a consequence may alter the duration and intensity of effects of drugs and neurotransmitters which are substrates for hOCT1.
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Citations
Cited by
Koepsell, H., Lips, K., & Volk, C. (2007) · Pharmaceutical Research · doi:10.1007/s11095-007-9254-z · Cited by 988
Self-citationTransporters and drug therapy: Implications for drug disposition and disease
HO, R., & KIM, R. (2005) · Clinical Pharmacology & Therapeutics · doi:10.1016/j.clpt.2005.05.011 · Cited by 502
Impact of Drug Transporter Studies on Drug Discovery and Development
Mizuno, N., Niwa, T., Yotsumoto, Y., & Sugiyama, Y. (2003) · Pharmacological Reviews · doi:10.1124/pr.55.3.1 · Cited by 490
Nies, A. T., Koepsell, H., Damme, K., & Schwab, M. (2011) · Handbook of Experimental Pharmacology · doi:10.1007/978-3-642-14541-4_3 · Cited by 375
Self-citationShu, Y., Leabman, M. K., Feng, B., Mangravite, L. M., Huang, C. C., Stryke, D., Kawamoto, M., Johns, S. J., DeYoung, J., Carlson, E., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0730858100 · Cited by 285
Metadata
- Authors
- Kerb, R., Brinkmann, U., Chatskaia, N., Gorbunov, D., Gorboulev, V., Mornhinweg, E., Keil, A., Eichelbaum, M., & Koepsell, H.
- Venue
- Pharmacogenetics
- Published
- 2002-11
- Volume
- 12
- Issue
- 8
- Pages
- 591-595
- ISSN
- 0960-314X (ISSN-L)
- OpenAlex
- W1980984502
- Cited by
- 214
- References
- 0
- FWCI
- 6.75
- Type
- journal article
- Language
- en
- Open access
- closed
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- Kerb, R., Brinkmann, U., Chatskaia, N., Gorbunov, D., Gorboulev, V., Mornhinweg, E., Keil, A., Eichelbaum, M., & Koepsell, H. (2002). Identification of genetic variations of the human organic cation transporter hOCT1 and their functional consequences. Pharmacogenetics. https://doi.org/10.1097/00008571-200211000-00002
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