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Interaction of Cisplatin with the Human Organic Cation Transporter 2
- Source :
- Clinical Cancer Research, 14(12), 3875-3880. American Association for Cancer Research Inc.
- Publication Year :
- 2008
- Publisher :
- American Association for Cancer Research (AACR), 2008.
-
Abstract
- Purpose: Cisplatin is predominantly eliminated in the urine through active secretion. As the solute carrier organic cation transporter 2 (OCT2) is highly expressed in the basolateral membrane of proximal tubules, we determined its contribution to cisplatin transport and assessed the relation of variation in the gene encoding OCT2 (SLC22A2) with the disposition of cisplatin. Experimental Design: Cell lines were transfected using the Flp-In 293 system with the full-length OCT2 cDNA, and platinum concentrations were measured using flameless atomic absorption spectrometry. Pharmacokinetic data were available from 106 cancer patients, and DNA was screened for eight nonsynonymous SLC22A2 variants using direct sequencing. Results: mRNA expression was 36-fold higher and uptake of the model substrate tetraethylammonium was significantly increased (P < 0.0001) in OCT2-transfected cells compared with empty vector-transfected controls. OCT2-mediated transport of cisplatin was saturable, and uptake was increased by ∼4-fold (P < 0.0001) relative to control cells. Cisplatin inhibited OCT2-mediated transport of tetraethylammonium by up to 97%. The mean ± SD systemic clearance of unbound cisplatin-derived platinum in the patient population was 29.2 ± 8.39 L/h, and renal clearance was particularly variable. Only one single nucleotide polymorphism (Ala270Se; rs316019) was identified (minor allele frequency, 7.6%), and it was not found to be associated with any of the studied pharmacokinetic variables (P > 0.05). Conclusion: These findings support the hypothesis that OCT2 is a key renal transporter involved in cisplatin elimination. However, known variants in SLC22A2 do not substantially contribute to explaining interindividual pharmacokinetic variability, suggesting that other mechanisms, controlling OCT2 expression, might be involved.
- Subjects :
- Male
Cancer Research
Genotype
Organic Cation Transport Proteins
Metabolic Clearance Rate
Antineoplastic Agents
Transfection
Polymorphism, Single Nucleotide
chemistry.chemical_compound
SDG 3 - Good Health and Well-being
Pharmacokinetics
Complementary DNA
medicine
Humans
Cells, Cultured
Cisplatin
Regulation of gene expression
Tetraethylammonium
Organic cation transport proteins
biology
Chemistry
Organic Cation Transporter 2
Up-Regulation
Solute carrier family
Gene Expression Regulation, Neoplastic
Phenotype
Oncology
Biochemistry
Inactivation, Metabolic
biology.protein
Female
medicine.drug
Subjects
Details
- ISSN :
- 15573265 and 10780432
- Volume :
- 14
- Database :
- OpenAIRE
- Journal :
- Clinical Cancer Research
- Accession number :
- edsair.doi.dedup.....f5fd7c6cd85e371b8371ec25d22e2ea0