Loss of multidrug resistance-associated protein 1 potentiates chronic doxorubicin-induced cardiac dysfunction in mice.
Doxorubicin (DOX), an effective cancer chemotherapeutic agent, induces dose-dependent cardiotoxicity, in part due to its ability to cause oxidative stress. We investigated the role of multidrug resistance-associated protein 1 (Mrp1/Abcc1) in DOX-induced cardiotoxicity in C57BL wild-type (WT) mice and their Mrp1 null (Mrp1(-/-)) littermates. Male mice were administered intraperitoneal DOX (3 or 2 mg/kg body weight) or saline twice a week for 3 weeks and examined 2 weeks after the last dose (protocol A total dose: 18 mg/kg) or for 5 weeks, and mice were examined 48 hours and 2 weeks after the last dose (protocol B total dose: 20 mg/kg). Chronic DOX induced body weight loss and hemotoxicity, adverse effects significantly exacerbated in Mrp1(-/-) versus WT mice. In the heart, significantly higher basal levels of glutathione (1.41-fold ± 0.27-fold) and glutathione disulfide (1.35-fold ± 0.16-fold) were detected in Mrp1(-/-) versus WT mice, and there were comparable decreases in the glutathione/glutathione disulfide ratio in WT and Mrp1(-/-) mice after DOX administration. Surprisingly, DOX induced comparable increases in 4-hydroxynonenal glutathione conjugate concentration in hearts from WT and Mrp1(-/-) mice. However, more DOX-induced apoptosis was detected in Mrp1(-/-) versus WT hearts (P < 0.05) (protocol A), and cardiac function, assessed by measurement of fractional shortening and ejection fraction with echocardiography, was significantly decreased by DOX in Mrp1(-/-) versus WT mice (P < 0.05; 95% confidence intervals of 20.0%-24.3% versus 23.7%-29.5% for fractional shortening, and 41.5%-48.4% versus 47.7%-56.7% for ejection fraction; protocol B). Together, these data indicate that Mrp1 protects the mouse heart against chronic DOX-induced cardiotoxicity.
Department of Toxicology and Cancer Biology (W.Z., J.D., D.S.C., M.V.), Division of Cardiovascular Medicine, (M.S., A.J.M), and Markey Cancer Center (C.W.), College of Medicine, University of Kentucky, Lexington, Kentucky.
Wei
W
Zhang
Department of Toxicology and Cancer Biology (W.Z., J.D., D.S.C., M.V.), Division of Cardiovascular Medicine, (M.S., A.J.M), and Markey Cancer Center (C.W.), College of Medicine, University of Kentucky, Lexington, Kentucky.
Jun
J
Deng
Department of Toxicology and Cancer Biology (W.Z., J.D., D.S.C., M.V.), Division of Cardiovascular Medicine, (M.S., A.J.M), and Markey Cancer Center (C.W.), College of Medicine, University of Kentucky, Lexington, Kentucky.
Manjula
M
Sunkara
Department of Toxicology and Cancer Biology (W.Z., J.D., D.S.C., M.V.), Division of Cardiovascular Medicine, (M.S., A.J.M), and Markey Cancer Center (C.W.), College of Medicine, University of Kentucky, Lexington, Kentucky.
Andrew J
AJ
Morris
Department of Toxicology and Cancer Biology (W.Z., J.D., D.S.C., M.V.), Division of Cardiovascular Medicine, (M.S., A.J.M), and Markey Cancer Center (C.W.), College of Medicine, University of Kentucky, Lexington, Kentucky.
Chi
C
Wang
Department of Toxicology and Cancer Biology (W.Z., J.D., D.S.C., M.V.), Division of Cardiovascular Medicine, (M.S., A.J.M), and Markey Cancer Center (C.W.), College of Medicine, University of Kentucky, Lexington, Kentucky.
Daret
D
St Clair
Department of Toxicology and Cancer Biology (W.Z., J.D., D.S.C., M.V.), Division of Cardiovascular Medicine, (M.S., A.J.M), and Markey Cancer Center (C.W.), College of Medicine, University of Kentucky, Lexington, Kentucky maryv@email.uky.edu.
Mary
M
Vore
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D017209:Apoptosis; D066126:Cardiotoxicity / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004317:Doxorubicin / Q000633:toxicity*; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D007958:Leukocyte Count; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D013599:Systole; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced / Q000503:physiopathology
D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D005978:Glutathione; D019803:Glutathione Disulfide; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C524061:glutathionyl 4-hydroxy-2-nonenal conjugate; C421109:multidrug resistance-associated protein 1