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Involvement of multidrug resistance-associated protein 1 in intestinal toxicity of methotrexate

Sayaka Kato1, Katsuaki Ito, Yukio Kato

  • 1Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa, Japan.

Pharmaceutical Research
|March 17, 2009
PubMed
Abstract

Insights

Multidrug resistance-associated protein 1 (MRP1) significantly contributes to methotrexate

Area of Science:

  • Pharmacology
  • Gastroenterology
  • Molecular Biology

Background:

  • Methotrexate (MTX) is a chemotherapy agent with dose-limiting gastrointestinal toxicity.
  • This toxicity is linked to intestinal tissue exposure and MTX being a substrate of multidrug resistance-associated protein 1 (MRP1).
  • MRP1 is highly expressed in the small intestine's proliferative crypt compartment.

Purpose of the Study:

  • To investigate the role of MRP1 in mediating MTX-induced gastrointestinal toxicity.
  • To determine if MRP1 expression influences MTX accumulation in intestinal cells.

Main Methods:

  • Administered MTX to MRP1 gene knockout (mrp1-/-) and wild-type (mrp1+/+) mice.
  • Monitored body weight, food/water intake, and performed intestinal histology.
  • Examined MTX pharmacokinetics and cellular accumulation.

Main Results:

  • MRP1 knockout mice exhibited more severe decreases in body weight and intake.
  • Intestinal histological studies revealed significant villi loss in MRP1 knockout mice compared to wild-type.
  • Higher MTX accumulation was observed in immature proliferative cells of MRP1 knockout mice.

Conclusions:

  • MRP1 plays a critical role in determining the exposure of intestinal proliferative cells to MTX.
  • This exposure mediated by MRP1 is a key factor in MTX-induced gastrointestinal toxicity.

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