Tissue and Cell Distribution of the Multidrug Resistance-Associated Protein (MRP) in Mouse Intestine and Kidney

Peng, Kou-Cheng; Cluzeaud, Françoise; Bens, Marcelle; Huyen, Jean–Paul Duong Van; Wioland, My Anh; Lacave, Roger; Vandewalle, Alain

doi:10.1177/002215549904700605

Cited by 130 publications

(106 citation statements)

References 37 publications

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“…4A). Peng et al reported that Mrp1 is highly expressed in proliferative cells of crypts in mouse small intestine (17), and this was supported by the immunohistochemical analysis performed in the present study (Fig. 4C).…”

Section: Although Transporter(s) Expressed In Differentiated Epithelisupporting

confidence: 90%

“…We focused on the localization of Mrp1 in proliferative cells in the small intestine (17), since MTX accumulation in such cells may be responsible for the severe intestinal toxicity observed in mrp1 (-/-) mice. In order to examine this possibility, the architecture of the small intestinal villi and the proliferation of the intestinal cells were investigated.…”

Section: Histological Changesmentioning

confidence: 99%

“…In the present study, we focused on the possible role of Mrp1, which accepts MTX as a substrate (16), in the intestinal toxicity of MTX. Mrp1 has been reported to be mainly localized in proliferative cells in crypts (17), and this led us to the hypothesis that Mrp1 is involved in active efflux of MTX from such proliferative cells as a defensive mechanism to protect the cells against toxicity arising from MTX treatment. To test this hypothesis, we compared the intestinal toxicity induced by MTX treatment in wild-type (mrp1 (+/+) ) and mrp1 gene knockout (mrp1 (-/-) ) mice in vivo.…”

Section: Introductionmentioning

confidence: 99%

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Involvement of Multidrug Resistance-Associated Protein 1 in Intestinal Toxicity of Methotrexate

et al. 2009

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1 ABSTRACTPurpose: Methotrexate (MTX) causes dose-limiting gastrointestinal toxicity due to exposure of intestinal tissues, and is a substrate of the multidrug resistance-associated protein (MRP) 1. Here we examine the involvement of MRP1, which is reported to be highly expressed in the proliferative crypt compartment of the small intestine, in the gastrointestinal toxicity of MTX.Methods: MTX was intraperitonealy administered to mrp1 gene knockout (mrp1 (-/-) ) and wild-type (mrp1 (+/+) ) mice. Body weight, food and water intake were monitored, intestinal histological studies and pharmacokinetics of MTX were examined. Results: mrp1(-/-) mice more severely decreased body weight, food and water intake than mrp1 (+/+) mice. Almost complete loss of villi throughout the small intestine in mrp1 (-/-) mice was observed, whereas the damage was only partial in mrp1 (+/+) mice. Plasma concentration and biliary excretion profiles of MTX were similar in mrp1 (-/-) and mrp1 (+/+) mice, though accumulation of MTX in immature proliferative cells isolated from mrp1 (-/-) mice was much higher compared to mrp1 (+/+) mice. Immunostaining revealed localization of Mrp1 in plasma membrane of the intestinal crypt compartment in mrp1 (+/+) mice, but not in mrp1 (-/-) mice. Conclusion:Mrp1 determines the exposure of proliferative cells in the small intestine to MTX, followed by gastrointestinal toxicity.

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Section: Although Transporter(s) Expressed In Differentiated Epithelisupporting

confidence: 90%

Section: Histological Changesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Involvement of Multidrug Resistance-Associated Protein 1 in Intestinal Toxicity of Methotrexate

et al. 2009

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“…Sugiyama and co-workers have shown MRP2 to be functionally expressed in Caco-2 and rodent intestine, transporting organic anions and glutathione conjugates in a blood-tolumen direction (Gotoh et al, 2000;Hirohashi et al, 2000). MRP1 and MRP3 are also expressed in intestinal cells although the functional signi®cance of these transporters remains to be determined (Peng et al, 1999;Ortiz et al, 1999;Hirohashi et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…MRP type transporters, studied primarily in over-expressing cell models, have the capacity to transport many substances including common drugs, often following enzymatic conjugation with glutathione, glucuronide or sulphate, although some MRPs may also act as unconjugated drug/glutathione co-transpor-ters Borst et al, 2000). Several members of the MRP family have been identi®ed at the molecular level in intestinal tissues (Mottino et al, 2000;Peng et al, 1999;Gotoh et al, 2000) and there is evidence that at least one of these, MRP2, is functionally active in this tissue (Gotoh et al, 2000). However, their contribution to intestinal drug e ux remains poorly de®ned.…”

Section: Introductionmentioning

confidence: 99%

Resolution of P‐glycoprotein and non‐P‐glycoprotein effects on drug permeability using intestinal tissues from mdr1a (−/−) mice

Stephens

O’Neill

Bennett

et al. 2002

British J Pharmacology

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1 Intestinal xenobiotic transporters are a signi®cant barrier to the absorption of many orally administered drugs. P-glycoprotein (PGP) is the best known, but several others, including members of the multidrug resistance-associated protein (MRP) family, are also expressed. De®nitive information on their precise e ect on intestinal drug permeability is scarce due to a lack of speci®c inhibitors and the di culty of studying non-PGP activity in the presence of high PGP expression. 2 We have investigated the in vitro use of intestinal tissues from PGP knockout (mdr1a (7/7)) mice as a tool for dissecting the mechanisms of intestinal drug e ux. The permeability characteristics of digoxin (DIG), paclitaxel (TAX) and etoposide (ETOP) were measured in ileum from mdr1a (7/7) and wild-type (FVB) mice mounted in Ussing chambers. 3 DIG and TAX exhibited marked e ux across FVB tissues (B-A : A-B apparent permeability (P app ) ratio 10 and 17 respectively) which was absent in mdr1a (7/7) tissues, con®rming that PGP is the sole route of intestinal e ux for these compounds. The A-B P app of both compounds was 3 ± 5 fold higher in mdr1a (7/7) than in FVB. 4 Polarized transport of ETOP in FVB tissues was reduced but not abolished in mdr1a (7/7) tissues. Residual ETOP e ux in mdr1a (7/7) tissues was abolished by the MRP inhibitor MK571, indicating involvement of both PGP and MRP. 5 MK571 abolished calcein e ux in mdr1a (7/7) tissues, while quinidine had no parallel e ect in FVB tissues, suggesting involvement of MRP but not PGP. 6 Tissues from mdr1a (7/7) mice provide a novel approach for investigating the in¯uence of PGP ablation on intestinal permeability and for resolving PGP and non-PGP mechanisms that modulate drug permeability.

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The use of transgenic mice in pharmacokinetic and pharmacodynamic studies

Elmquist¹,

Miller²

2001

Journal of Pharmaceutical Sciences

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Tissue and Cell Distribution of the Multidrug Resistance-Associated Protein (MRP) in Mouse Intestine and Kidney

Cited by 130 publications

References 37 publications

Involvement of Multidrug Resistance-Associated Protein 1 in Intestinal Toxicity of Methotrexate

Involvement of Multidrug Resistance-Associated Protein 1 in Intestinal Toxicity of Methotrexate

Resolution of P‐glycoprotein and non‐P‐glycoprotein effects on drug permeability using intestinal tissues from mdr1a (−/−) mice

The use of transgenic mice in pharmacokinetic and pharmacodynamic studies

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