Influence of Slco2b1-knockout and SLCO2B1-humanization on coproporphyrin I and III levels in rats.
OATP2B1
coproporphyrin
drug transporter
humanized
in vivo
knockout
rat
Journal
British journal of pharmacology
ISSN: 1476-5381
Titre abrégé: Br J Pharmacol
Pays: England
ID NLM: 7502536
Informations de publication
Date de publication:
Jan 2024
Jan 2024
Historique:
revised:
15
03
2023
received:
25
10
2022
accepted:
20
07
2023
medline:
6
12
2023
pubmed:
3
8
2023
entrez:
3
8
2023
Statut:
ppublish
Résumé
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. 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 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 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.
Sections du résumé
BACKGROUND AND PURPOSE
OBJECTIVE
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
METHODS
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
KEY RESULTS
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
CONCLUSION AND IMPLICATIONS
CONCLUSIONS
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.
Substances chimiques
coproporphyrin I
531-14-6
Coproporphyrins
0
Organic Anion Transporters
0
Membrane Transport Proteins
0
SLCO2B1 protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
36-53Informations de copyright
© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
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