Influence of Slco2b1-knockout and SLCO2B1-humanization on coproporphyrin I and III levels in rats
© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society..
BACKGROUND AND PURPOSE: Coproporphyrin (CP) I and III are byproducts of haem synthesis currently investigated as biomarkers for drug-drug interactions involving hepatic organic anion transporting polypeptide (OATP) 1B transporters. Another hepatically expressed OATP-member is OATP2B1. The aim of this study was to test the impact of OATP2B1, which specifically transports CPIII, on CP serum levels, applying novel rat models.
EXPERIMENTAL APPROACH: CPIII transport kinetics and the interplay between OATP2B1 and multidrug resistance-associated proteins (MRPs) were determined in vitro using the vTF7 expression system. Novel rSlco2b1-/- and SLCO2B1+/+ rat models were characterized for physiological parameters and for CP serum levels. Hepatic and renal expression of transporters involved in CP disposition were determined by real-time qPCR, Western blot analysis, and immunohistochemistry.
KEY RESULTS: In vitro experiments revealed differences in transport kinetics comparing human and rat OATP2B1 and showed a consistent, species-specific interplay with hMRP3/rMRP3. Deletion of rOATP2B1 was associated with a trend towards lower CPI serum levels compared with wildtype rats, while CPIII remained unchanged. Comparing SLCO2B1+/+ with knockout rats revealed an effect of sex: only in females the genetic modification influenced CP serum levels. Analysis of hepatic and renal transporters revealed marginal, but in part, statistically significant differences in rMRP2 abundance, which may contribute to the observed changes in CP serum levels.
CONCLUSION AND IMPLICATIONS: Our findings support that factors other than OATP1B transporters are of relevance for basal CP levels. Only in female rats, humanization of SLCO2B1 affects basal CPI and CPIII serum levels, despite isomer selectivity of OATP2B1.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:181 |
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| Enthalten in: |
British journal of pharmacology - 181(2024), 1 vom: 06. Jan., Seite 36-53 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kinzi, Jonny [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 15.12.2023 Date Revised 06.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1111/bph.16205 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Kinzi, Jonny |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Influence of Slco2b1-knockout and SLCO2B1-humanization on coproporphyrin I and III levels in rats |
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| 500 | |a Date Revised 06.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. | ||
| 520 | |a BACKGROUND AND PURPOSE: Coproporphyrin (CP) I and III are byproducts of haem synthesis currently investigated as biomarkers for drug-drug interactions involving hepatic organic anion transporting polypeptide (OATP) 1B transporters. Another hepatically expressed OATP-member is OATP2B1. The aim of this study was to test the impact of OATP2B1, which specifically transports CPIII, on CP serum levels, applying novel rat models | ||
| 520 | |a EXPERIMENTAL APPROACH: CPIII transport kinetics and the interplay between OATP2B1 and multidrug resistance-associated proteins (MRPs) were determined in vitro using the vTF7 expression system. Novel rSlco2b1-/- and SLCO2B1+/+ rat models were characterized for physiological parameters and for CP serum levels. Hepatic and renal expression of transporters involved in CP disposition were determined by real-time qPCR, Western blot analysis, and immunohistochemistry | ||
| 520 | |a KEY RESULTS: In vitro experiments revealed differences in transport kinetics comparing human and rat OATP2B1 and showed a consistent, species-specific interplay with hMRP3/rMRP3. Deletion of rOATP2B1 was associated with a trend towards lower CPI serum levels compared with wildtype rats, while CPIII remained unchanged. Comparing SLCO2B1+/+ with knockout rats revealed an effect of sex: only in females the genetic modification influenced CP serum levels. Analysis of hepatic and renal transporters revealed marginal, but in part, statistically significant differences in rMRP2 abundance, which may contribute to the observed changes in CP serum levels | ||
| 520 | |a CONCLUSION AND IMPLICATIONS: Our findings support that factors other than OATP1B transporters are of relevance for basal CP levels. Only in female rats, humanization of SLCO2B1 affects basal CPI and CPIII serum levels, despite isomer selectivity of OATP2B1 | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Schäfer, Anima M |e verfasserin |4 aut | |
| 700 | 1 | |a Treyer, Andrea |e verfasserin |4 aut | |
| 700 | 1 | |a Seibert, Isabell |e verfasserin |4 aut | |
| 700 | 1 | |a Tillmann, Annika |e verfasserin |4 aut | |
| 700 | 1 | |a Mueller, Vanessa |e verfasserin |4 aut | |
| 700 | 1 | |a Gherardi, Clarisse |e verfasserin |4 aut | |
| 700 | 1 | |a Vonwyl, Celina |e verfasserin |4 aut | |
| 700 | 1 | |a Hamburger, Matthias |e verfasserin |4 aut | |
| 700 | 1 | |a Meyer Zu Schwabedissen, Henriette E |e verfasserin |4 aut | |
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