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Role of ABCC1 in protecting the heart against doxorubicin (DOX)‐induced oxidative stress

We investigated the role of multidrug resistance‐associated protein 1 (Mrp1), an ATP‐binding cassette transporter (ABCC1), in mouse heart following DOX‐induced oxidative stress. Wildtype (WT) and Mrp1−/− (KO) C57BL/6 littermates were administered a single dose of 20 mg/kg DOX or Saline (SAL) intravenously. Hearts were collected 72 h later, and ultrastructural damage measured by electron microscopy (EM) (n=6) and content of the glutathione conjugate of 4‐hydroxynonenal (GS‐HNE), a substrate of Mrp1, determined by LC‐MS (n=6–7). The mRNA of Nrf2 responsive genes, Nqo1, GPX1, GPX3, and GPX4 were quantitated by real time quantitative PCR (n=6). Morphometric analysis of EM data showed a trend (p = 0.063) for decreased cytoplasmic + mitochondrial damage in DOX‐treated KO mice vs WT, but increased (p = 0.031) nuclear injury in KO mice. In contrast, SAL induced more cytoplasmic damage in KO mice (p = 0.015). GS‐HNE (nmol/g heart tissue) of WT and KO SAL mice were similar, whereas DOX decreased (p < 0.001) GS‐HNE in WT mice, but had no effect in KO mice. The basal level of GS‐HNE in naïve KO mice was lower (p = 0.013) than in naive WT mice (n=8). DOX increased mRNA of Nqo1 and GPX3 in hearts of WT and KO mice similarly, but had little influence on GPX1 and GPX4 mRNA. Nevertheless, in naïve mice, basal levels of Nqo1, GPX3, and GPX4 mRNA were lower in KO than in WT (p = 0.001, 0.011, 0.022, respectively). These data imply that the elevated GSH level in hearts of KO mice is able to protect against some forms of DOX‐induced injury, but not others. (CA139844)