Aging downregulates MRPs and increases cardiac doxorubicin accumulation

Abstract

Doxorubicin (DOX) is a common antineoplastic agent used to treat cancer patients of all ages. The primary side effect of DOX treatment is a dose‐dependent cardiotoxicity, which is developed in a more delayed manner in children. Multidrug resistant protein‐1, ‐2, and ‐7 (MRP‐1, ‐2, ‐7) are known to extrude DOX and may factor into the degree of cardiac DOX accumulation. The purpose of this study was to examine age‐related differences in cardiac MRP expression and DOX accumulation. Female Sprague‐Dawley rats were randomly selected to receive a 15 mg DOX/kg body weight (i.p.) at 4, 8, 12, 16, 20 or 24 weeks of age. Animals were sacrificed 24 hours following injection and hearts were excised, flushed of blood, and left ventricles (LV) were isolated. High performance liquid chromatography was utilized to quantify DOX and Western blotting to analyze MRP expression. DOX accumulation was lowest in 4‐week (675±183 ng DOX/g LV) and 8‐week old animals (724±247 ng DOX/g LV) and was significantly increased (p<0.05) at 12‐weeks (992±304 ng DOX/g LV) and 16‐weeks (1068±348 ng DOX/g LV) as well as 20‐weeks (1440±226 ng DOX/g LV) and 24‐weeks (1321±247 ng DOX/g LV). A significant downregulation (p<0.05) of MRP‐2 (3‐fold) and MRP‐7 (4‐fold) expression was seen with increasing age while no differences in MRP‐1 expression were observed. These data suggest that MRP‐2 and MRP‐7 expression may play a role with increased DOX accumulation with age.