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Drug Metab Dispos. 2008 Aug;36(8):1722-8. doi: 10.1124/dmd.108.021881. Epub 2008 May 7.

Deletion of the NADPH-cytochrome P450 reductase gene in cardiomyocytes does not protect mice against doxorubicin-mediated acute cardiac toxicity.

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1
Wadsworth Center, New York State Department of Health, Empire State Plaza, Albany, NY, USA.

Abstract

A genetic mouse model (designated cardiomyocyte-Cpr-null) with cardiomyocyte-specific deletion of the cytochrome P450 (P450) reductase (Cpr) gene was generated in this study. CPR protein levels, as well the enzyme activity of P450s, were greatly reduced in heart microsomes from the null mice compared with wild-type mice, whereas CPR expression in other organs remained unchanged. Nonetheless, homozygous null mice were normal in appearance, gross anatomy, tissue morphology, and general cardiac functional parameters, and there was no indication of embryonic lethality or premature mortality in contrast to the recognized role of CPR in embryonic development. Thus, this new mouse model should be useful for determination of the in vivo roles of cardiomyocyte CPR and CPR-dependent enzymes, including microsomal P450s, not only in the metabolism and toxicity of numerous xenobiotic compounds but also in cardiac pathophysiology. As a first application, we studied the role of cardiomyocyte CPR and CPR-dependent enzymes in doxorubicin (Dox)-mediated acute cardiotoxicity. Wild-type and null mice were treated with a single i.p. dose of Dox at 5, 10, or 20 mg/kg. The Dox treatment caused apoptosis and vacuolization in cardiomyocytes at the dose of 20 mg/kg and a significant increase in the levels of serum creatine kinase at 10 and 20 mg/kg in both wild-type and null mice. However, there was no significant difference in the extent of Dox-induced cardiac injury between the two strains; this lack of difference suggests that cardiomyocyte CPR and CPR-dependent enzymes do not play critical roles in the acute cardiotoxicity induced by Dox.

PMID:
18463197
PMCID:
PMC2575052
DOI:
10.1124/dmd.108.021881
[Indexed for MEDLINE]
Free PMC Article
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