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

Abstract

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.

Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation

“…Although the plasma concentration and biliary excretion of methotrexate are unchanged, immature proliferative cells from Mrp1-null mice have higher methotrexate accumulation compared with wild type (Kato et al, 2009).…”

“…TRANSPORTER FUNCTION AND REGULATION hanced sensitivity to the gastrointestinal toxicity of methotrexate, as exhibited by nearly complete loss of small intestinal villi (Kato et al, 2009). Although the plasma concentration and biliary excretion of methotrexate are unchanged, immature proliferative cells from Mrp1-null mice have higher methotrexate accumulation compared with wild type (Kato et al, 2009).…”

Chalcogenopyrylium Dyes as Differential Modulators of Organic Anion Transport by Multidrug Resistance Protein 1 (MRP1), MRP2, and MRP4

“…Similar to P-glycoprotein, MRP1 can confer resistance to natural product drugs in tumor cells (Cole et al, 1994). It also plays a different but still protective role in normal tissues because it is expressed at the interface of various so-called pharmacological sanctuary sites, including the blood-cerebrospinal fluid barrier (Wijnholds et al, 2000;Kato et al, 2009). Unlike P-glycoprotein, however, MRP1 is an efficient transporter of numerous organic anions, many of which are glutathione or glucuronide conjugates of drug metabolites (Leslie et al, 2005;Slot et al, 2011).…”

Oral Availability of Cefadroxil Depends on ABCC3 and ABCC4

“…Therefore, the localization of Abcc1 argues against a role of Abcc1 in the basolateral efflux of cefadroxil in enterocytes. However, we can not fully exclude that there is a role of Abcc1 in the efflux of cefadroxil because this transporter protects against the intestinal toxicity evoked by methotrexate (Kato et al, 2009). This means that Abcc1 is pumping methotrexate out of the cell at a physiological relevant speed.…”

“…2 and 3). However, Abcc1 is expressed in the small intestine, mainly in the crypts (Peng et al, 1999;Kato et al, 2009), which does not colocalize with PepT1, which is abundantly present in the villus tip with decreasing levels toward the villus base. Therefore, the localization of Abcc1 argues against a role of Abcc1 in the basolateral efflux of cefadroxil in enterocytes.…”