Induction of several cytochrome P450 genes by doxorubicin in H9c2 cells.
Doxorubicin is a potent anti-neoplastic antibiotic used to treat a wide variety of malignancies; however, its use is limited by dose dependent cardiotoxicity. There is indirect evidence suggesting that doxorubicin cardiotoxicity is CYP-mediated. In the current study, we investigated the effect of doxorubicin on hypertrophic markers, and different CYP gene expression in cardiac derived H9c2 cells. H9c2 cells were incubated with increasing concentrations of doxorubicin and the expressions of different genes were determined by real-time PCR. Our results demonstrate that multiple CYP genes are expressed in H9c2 cells and the level of expression from the highest to the lowest were; CYP1B1, CYP2B1, CYP2J3, CYP1A1, CYP2C11, CYP2C23, CYP2E1, CYP1A2, and CYP2B2. Doxorubicin treatment caused an induction of the hypertrophic markers, ANP and BNP. In addition, doxorubicin caused a significant induction of CYP1A1, CYP1A2, CYP1B1, CYP2B2, CYP2E1, and CYP2J3 gene expression in a concentration-dependent manner. However, only the highest concentration tested, 10 muM, caused an induction of CYP2C11; whereas, CYP2B1 and CYP2C23 were not altered. Our findings demonstrate that doxorubicin induces the hypertrophic markers, ANP and BNP as well as several CYP genes in H9c2 cells. Doxorubicin-mediated CYP induction may represent a novel mechanism by which this drug induces cardiotoxicity.
Zordoky
Beshay N M
BN
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2N8.
El-Kadi
Ayman O S
AO
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D007527:Isoenzymes / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000903:Antibiotics, Antineoplastic; D007527:Isoenzymes; D004317:Doxorubicin; D003577:Cytochrome P-450 Enzyme System