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Site-specific bidirectional efflux of 2,4-dinitrophenyl-S-glutathione, a substrate of multidrug resistance-associated proteins, in rat intestine and Caco-2 cells.
J Pharm Pharmacol. 2007 Apr; 59(4):513-20.JP

Abstract

The site-specific function of multidrug-resistance-associated proteins (MRPs), especially MRP2 and MRP3, was examined in rat intestine and human colon adenocarcinoma (Caco-2) cells. The MRP function was evaluated pharmacokinetically by measuring the efflux transport of 2,4-dinitrophenyl-S-glutathione (DNP-SG), an MRP substrate, after application of 1-chloro-2,4-dinitrobenzene (CDNB), a precursor of DNP-SG. The expression of rat and human MRP2 and MRP3 was analysed by Western blotting. The rat jejunum exhibited a higher apical MRP2 and a lower basolateral MRP3 expression than ileum. In accordance with the expression level, DNP-SG efflux to the mucosal surface was significantly greater in jejunum, while serosal efflux was greater in ileum. Site-specific bidirectional efflux of DNP-SG was also observed in in-vivo studies, in which portal and femoral plasma levels and biliary excretion rate of DNP-SG were significantly higher when CDNB was administered to ileum. Caco-2 cells also showed a bidirectional efflux of DNP-SG. Probenecid, an MRP inhibitor, significantly suppressed the mucosal efflux in jejunum and serosal efflux in ileum. In contrast, probenecid significantly suppressed both apical and basolateral efflux of DNP-SG in Caco2 cells, though the inhibition was of small magnitude. In conclusion, the efflux of DNP-SG from enterocytes mediated by MRPs exhibited a significant regional difference in rat intestine, indicating possible variability in intestinal bioavailabilities of MRP substrates, depending on their absorption sites along the intestine.

Authors+Show Affiliations

Department of Pharmaceutics and Therapeutics, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

17430634

Citation

Yokooji, Tomoharu, et al. "Site-specific Bidirectional Efflux of 2,4-dinitrophenyl-S-glutathione, a Substrate of Multidrug Resistance-associated Proteins, in Rat Intestine and Caco-2 Cells." The Journal of Pharmacy and Pharmacology, vol. 59, no. 4, 2007, pp. 513-20.
Yokooji T, Murakami T, Yumoto R, et al. Site-specific bidirectional efflux of 2,4-dinitrophenyl-S-glutathione, a substrate of multidrug resistance-associated proteins, in rat intestine and Caco-2 cells. J Pharm Pharmacol. 2007;59(4):513-20.
Yokooji, T., Murakami, T., Yumoto, R., Nagai, J., & Takano, M. (2007). Site-specific bidirectional efflux of 2,4-dinitrophenyl-S-glutathione, a substrate of multidrug resistance-associated proteins, in rat intestine and Caco-2 cells. The Journal of Pharmacy and Pharmacology, 59(4), 513-20.
Yokooji T, et al. Site-specific Bidirectional Efflux of 2,4-dinitrophenyl-S-glutathione, a Substrate of Multidrug Resistance-associated Proteins, in Rat Intestine and Caco-2 Cells. J Pharm Pharmacol. 2007;59(4):513-20. PubMed PMID: 17430634.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Site-specific bidirectional efflux of 2,4-dinitrophenyl-S-glutathione, a substrate of multidrug resistance-associated proteins, in rat intestine and Caco-2 cells. AU - Yokooji,Tomoharu, AU - Murakami,Teruo, AU - Yumoto,Ryoko, AU - Nagai,Junya, AU - Takano,Mikihisa, PY - 2007/4/14/pubmed PY - 2007/6/15/medline PY - 2007/4/14/entrez SP - 513 EP - 20 JF - The Journal of pharmacy and pharmacology JO - J Pharm Pharmacol VL - 59 IS - 4 N2 - The site-specific function of multidrug-resistance-associated proteins (MRPs), especially MRP2 and MRP3, was examined in rat intestine and human colon adenocarcinoma (Caco-2) cells. The MRP function was evaluated pharmacokinetically by measuring the efflux transport of 2,4-dinitrophenyl-S-glutathione (DNP-SG), an MRP substrate, after application of 1-chloro-2,4-dinitrobenzene (CDNB), a precursor of DNP-SG. The expression of rat and human MRP2 and MRP3 was analysed by Western blotting. The rat jejunum exhibited a higher apical MRP2 and a lower basolateral MRP3 expression than ileum. In accordance with the expression level, DNP-SG efflux to the mucosal surface was significantly greater in jejunum, while serosal efflux was greater in ileum. Site-specific bidirectional efflux of DNP-SG was also observed in in-vivo studies, in which portal and femoral plasma levels and biliary excretion rate of DNP-SG were significantly higher when CDNB was administered to ileum. Caco-2 cells also showed a bidirectional efflux of DNP-SG. Probenecid, an MRP inhibitor, significantly suppressed the mucosal efflux in jejunum and serosal efflux in ileum. In contrast, probenecid significantly suppressed both apical and basolateral efflux of DNP-SG in Caco2 cells, though the inhibition was of small magnitude. In conclusion, the efflux of DNP-SG from enterocytes mediated by MRPs exhibited a significant regional difference in rat intestine, indicating possible variability in intestinal bioavailabilities of MRP substrates, depending on their absorption sites along the intestine. SN - 0022-3573 UR - https://www.unboundmedicine.com/medline/citation/17430634/Site_specific_bidirectional_efflux_of_24_dinitrophenyl_S_glutathione_a_substrate_of_multidrug_resistance_associated_proteins_in_rat_intestine_and_Caco_2_cells_ L2 - https://doi.org/10.1211/jpp.59.4.0005 DB - PRIME DP - Unbound Medicine ER -