The influence of ABCG2 polymorphism on erlotinib efflux in the K562 cell line
Abstract Single nucleotide polymorphisms (SNPs) in the gene for multidrug resistance protein ABCG2, an erlotinib transporter, is a possible contributor to the interindividual variation observed in erlotinib pharmacokinetics and toxicity. Therefore, the aim was to study erlotinib efflux by ABCG2 wild...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2020-04-01
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| Series: | Pharmacology Research & Perspectives |
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| Online Access: | https://doi.org/10.1002/prp2.581 |
| _version_ | 1818617632894484480 |
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| author | Anna Svedberg Lianne Jacobs Svante Vikingsson Henrik Gréen |
| author_facet | Anna Svedberg Lianne Jacobs Svante Vikingsson Henrik Gréen |
| author_sort | Anna Svedberg |
| collection | DOAJ |
| description | Abstract Single nucleotide polymorphisms (SNPs) in the gene for multidrug resistance protein ABCG2, an erlotinib transporter, is a possible contributor to the interindividual variation observed in erlotinib pharmacokinetics and toxicity. Therefore, the aim was to study erlotinib efflux by ABCG2 wild‐type (wt) and ABCG2 polymorphic variants in the K562 cell line. The chronic myeloid leukemia K562 cell line, neither expressing EGFR nor ABCG2, was transduced with vectors containing the ABCG2 wt, the SNPs: 34 G > A and 421 C > A, or with empty vector (K562/ve). ABCG2‐expressing cells were enriched using magnetic sorting and the expression was verified using flow cytometry. Intracellular erlotinib concentrations were analyzed by LC–MS/MS after incubation with 1 µmol/L erlotinib for 60 minutes. All recombinant cell lines were confirmed carriers of the vector and expressed ABCG2. Differences in intracellular erlotinib concentrations were observed between K562/ve and K562 ABCG2 wt and between K562/ve and K562 ABCG2 34G > A (both P ≤ .001, one‐way ANOVA with Tukey HSD post hoc test), indicating that the cell lines carrying ABCG2 wt and ABCG2 34G > A actively transports erlotinib out of the cells. The ABCG2 34G > A cell line had a higher transport capacity compared with ABCG2 wt after adjusting for ABCG2 expression (P = .024, t test). No differences were observed between K562/ve and K562 ABCG2 421 C > A. Genetic polymorphism in the ABCG2 gene has an influence on the transport of erlotinib which can contribute to the observed variation in erlotinib pharmacokinetics and toxicity. |
| first_indexed | 2024-12-16T17:08:47Z |
| format | Article |
| id | doaj.art-d0d91edf08ab49358932c31a3b343be6 |
| institution | Directory Open Access Journal |
| issn | 2052-1707 |
| language | English |
| last_indexed | 2024-12-16T17:08:47Z |
| publishDate | 2020-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Pharmacology Research & Perspectives |
| spelling | doaj.art-d0d91edf08ab49358932c31a3b343be62022-12-21T22:23:29ZengWileyPharmacology Research & Perspectives2052-17072020-04-0182n/an/a10.1002/prp2.581The influence of ABCG2 polymorphism on erlotinib efflux in the K562 cell lineAnna Svedberg0Lianne Jacobs1Svante Vikingsson2Henrik Gréen3Clinical Pharmacology Division of Drug Research Department of Medical and Health Sciences Linköping University Linköping SwedenClinical Pharmacology Division of Drug Research Department of Medical and Health Sciences Linköping University Linköping SwedenClinical Pharmacology Division of Drug Research Department of Medical and Health Sciences Linköping University Linköping SwedenClinical Pharmacology Division of Drug Research Department of Medical and Health Sciences Linköping University Linköping SwedenAbstract Single nucleotide polymorphisms (SNPs) in the gene for multidrug resistance protein ABCG2, an erlotinib transporter, is a possible contributor to the interindividual variation observed in erlotinib pharmacokinetics and toxicity. Therefore, the aim was to study erlotinib efflux by ABCG2 wild‐type (wt) and ABCG2 polymorphic variants in the K562 cell line. The chronic myeloid leukemia K562 cell line, neither expressing EGFR nor ABCG2, was transduced with vectors containing the ABCG2 wt, the SNPs: 34 G > A and 421 C > A, or with empty vector (K562/ve). ABCG2‐expressing cells were enriched using magnetic sorting and the expression was verified using flow cytometry. Intracellular erlotinib concentrations were analyzed by LC–MS/MS after incubation with 1 µmol/L erlotinib for 60 minutes. All recombinant cell lines were confirmed carriers of the vector and expressed ABCG2. Differences in intracellular erlotinib concentrations were observed between K562/ve and K562 ABCG2 wt and between K562/ve and K562 ABCG2 34G > A (both P ≤ .001, one‐way ANOVA with Tukey HSD post hoc test), indicating that the cell lines carrying ABCG2 wt and ABCG2 34G > A actively transports erlotinib out of the cells. The ABCG2 34G > A cell line had a higher transport capacity compared with ABCG2 wt after adjusting for ABCG2 expression (P = .024, t test). No differences were observed between K562/ve and K562 ABCG2 421 C > A. Genetic polymorphism in the ABCG2 gene has an influence on the transport of erlotinib which can contribute to the observed variation in erlotinib pharmacokinetics and toxicity.https://doi.org/10.1002/prp2.581ABCG2erlotinibLC–MS/MSpolymorphismtransport |
| spellingShingle | Anna Svedberg Lianne Jacobs Svante Vikingsson Henrik Gréen The influence of ABCG2 polymorphism on erlotinib efflux in the K562 cell line Pharmacology Research & Perspectives ABCG2 erlotinib LC–MS/MS polymorphism transport |
| title | The influence of ABCG2 polymorphism on erlotinib efflux in the K562 cell line |
| title_full | The influence of ABCG2 polymorphism on erlotinib efflux in the K562 cell line |
| title_fullStr | The influence of ABCG2 polymorphism on erlotinib efflux in the K562 cell line |
| title_full_unstemmed | The influence of ABCG2 polymorphism on erlotinib efflux in the K562 cell line |
| title_short | The influence of ABCG2 polymorphism on erlotinib efflux in the K562 cell line |
| title_sort | influence of abcg2 polymorphism on erlotinib efflux in the k562 cell line |
| topic | ABCG2 erlotinib LC–MS/MS polymorphism transport |
| url | https://doi.org/10.1002/prp2.581 |
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