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

Cheng Fang; Jun Gu; Fang Xie; Melissa Behr; Weizhu Yang; E Dale Abel; Xinxin Ding

doi:10.1124/dmd.108.021881

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

Journal article

Peer reviewed

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

Cheng Fang, Jun Gu, Fang Xie, Melissa Behr, Weizhu Yang, E Dale Abel and Xinxin Ding

Drug metabolism and disposition, Vol.36(8), pp.1722-1728

08/2008

DOI: 10.1124/dmd.108.021881

PMCID: PMC2575052

PMID: 18463197

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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.

Apoptosis

Immunohistochemistry

Myocardium - enzymology

NADPH-Ferrihemoprotein Reductase - genetics

Animals

Heart - drug effects

Mice

Doxorubicin - toxicity

Antineoplastic Agents - toxicity

Details

Title: Subtitle: Deletion of the NADPH-cytochrome P450 reductase gene in cardiomyocytes does not protect mice against doxorubicin-mediated acute cardiac toxicity
Creators: Cheng Fang - Wadsworth Center, New York State Department of Health, Empire State Plaza, Albany, NY, USA
Jun Gu
Fang Xie
Melissa Behr
Weizhu Yang
E Dale Abel
Xinxin Ding - State University of New York
Resource Type: Journal article
Publication Details: Drug metabolism and disposition, Vol.36(8), pp.1722-1728
DOI: 10.1124/dmd.108.021881
PMID: 18463197
PMCID: PMC2575052
NLM abbreviation: Drug Metab Dispos
ISSN: 0090-9556
eISSN: 1521-009X
Publisher: United States
Grant note: ES07462 / NIEHS NIH HHS R01 ES007462-13 / NIEHS NIH HHS R01 HL070070-04 / NHLBI NIH HHS HL70070 / NHLBI NIH HHS R01 HL070070 / NHLBI NIH HHS R01 ES007462 / NIEHS NIH HHS R01 DK092065 / NIDDK NIH HHS
Language: English
Date published: 08/2008
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984024501702771

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