Potency and mechanism of p-glycoprotein chemosensitizers in rainbow trout (Oncorhynchus mykiss) hepatocytes.
Chemosensitizer
Hepatocytes
P-glycoprotein
Rainbow trout
Journal
Fish physiology and biochemistry
ISSN: 1573-5168
Titre abrégé: Fish Physiol Biochem
Pays: Netherlands
ID NLM: 100955049
Informations de publication
Date de publication:
19 Jul 2024
19 Jul 2024
Historique:
received:
31
08
2023
accepted:
02
07
2024
medline:
19
7
2024
pubmed:
19
7
2024
entrez:
18
7
2024
Statut:
aheadofprint
Résumé
The membrane efflux transporter P-glycoprotein (P-gp, [ABCB1, MDR1]) exports a wide range of xenobiotic compounds, resulting in a continuous first line of defense against toxicant accumulation at basal expression levels, and contributing to the multixenobiotic resistance (MXR) phenotype at elevated expression levels. Relatively little information exists on P-gp inhibition in fish by chemosensitizers, compounds which lower toxicity thresholds for harmful P-gp substrates in complex mixtures. The effects of four known mammalian chemosensitizers (cyclosporin A [CsA], quinidine, valspodar [PSC833], and verapamil) on the P-gp-mediated transport of rhodamine 123 (R123) and cortisol in primary cultures of rainbow trout (Oncorhynchus mykiss) hepatocytes were examined. Competitive accumulation assays using 25 µM R123 or cortisol and varying concentrations of chemosensitizers (0-500 µM) were used. CsA, quinidine, and verapamil inhibited R123 export (IC50 values ± SE: 132 ± 60, 83.3 ± 27.2, and 43.2 ± 13.6 µM, respectively). CsA and valspodar inhibited cortisol export (IC50 values: 294 ± 106 and 92.2 ± 34.9 µM, respectively). In an ATP depletion assay, hepatocytes incubated with all four chemosensitizers resulted in lower free ATP concentrations, suggesting that they act via competitive inhibition. Chemosensitizers that inhibit MXR transporters are an important class of environmental pollutant, and these results show that rainbow trout transporters are inhibited by similar chemosensitizers (and mostly at similar concentrations) as seen in mammals and other fish species.
Identifiants
pubmed: 39026113
doi: 10.1007/s10695-024-01376-9
pii: 10.1007/s10695-024-01376-9
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Natural Sciences and Engineering Research Council of Canada
ID : R611305
Informations de copyright
© 2024. The Author(s), under exclusive licence to Springer Nature B.V.
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