Clin Res Cardiol 96: Suppl 1 (2007)

V1479 - Upregulation of P-glycoprotein and BCRP in murine heart after doxorubicin treatment
 
J. Haney1, M. Grube1, S. Bien1, A. Riad2, C. Tschöpe2, H. P. Schultheiss2, G. Jedlitschky1, H.K. Kroemer1
 
1Institut für Pharmakologie, Universität Greifswald, Greifswald; 2Med. Klinik II, Abt. für Kardiologie und Pulmologie, Charité - Universitätsmedizin Berlin, Campus Benj. Franklin, Berlin;
 
Background: ATP-dependent efflux transporters of the ABC-superfamily have been identified in a variety of different tissues in man and mouse. While these proteins are part of physiological barriers like in the brain and the gut, they are also responsible for multidrug resistance in cancer therapy. With regard to their substrate spectrum, which contains for example anticancer, cardiovascular and antiepileptic drugs, we are interested in the expression of these proteins in human heart, especially after exposure to doxorubicin, which therapeutic use is limited by cardiotoxic side effects (cardiomyopathy). In this context, the ABC-transporters P-glycoprotein (P-gp, mdr1) and breast cancer resistance protein (BCRP) are interesting candidates; because both transporters have been demonstrated to be expressed in heart and both P-gp and a variant of BCRP have been shown to transport doxorubicin. We therefore investigated the expression of these transporters in heart samples of doxorubicin treated mice.
Methods/Results: C57Bl/10 mice were treated with doxorubicin (20 mg/kg body weight, intraperitoneally). Hearts of these mice as well as of untreated control animals were investigated after one, three and five days of doxorubicin administration. Gene expression was measured using real-time PCR technology. Here, we could demonstrate an increased P-gp (mdr1a) and bcrp expression after doxorubicin administration with the most pronounced effect after 3d (mdr1a: 139% (1d), 161% (3d), 80% (5d) of control, bcrp: 150%, 250%, 122% of control). Additional in vitro experiments using the murine cardiomyocyte cell line HL1 confirmed these results. Furthermore, using this cellular model system we were able to verify these regulations on protein level, too.
Conclusion: The mRNA expression of the ABC transporter mdr1a and bcrp could be demonstrated in normal and doxorubicin treated murine heart samples. Furthermore, we observed an altered mRNA expression; both proteins were upregulated after doxorubicin exposure. This finding may be important for the uptake cardiovascular drugs and furthermore may influence the intracardiac concentration of doxorubicin, which in turn may be relevant for the expected site effects after or during chemotherapy.
 

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