title: Glutathione S-transferase P protects against cyclophosphamide-induced cardiotoxicity in mice.
abstract: High-dose chemotherapy regimens using cyclophosphamide (CY) are frequently associated with cardiotoxicity that could lead to myocyte damage and congestive heart failure. However, the mechanisms regulating the cardiotoxic effects of CY remain unclear. Because CY is converted to an unsaturated aldehyde acrolein, a toxic, reactive CY metabolite that induces extensive protein modification and myocardial injury, we examined the role of glutathione S-transferase P (GSTP), an acrolein-metabolizing enzyme, in CY cardiotoxicity in wild-type (WT) and GSTP-null mice. Treatment with CY (100-300 mg/kg) increased plasma levels of creatine kinase-MB isoform (CK · MB) and heart-to-body weight ratio to a significantly greater extent in GSTP-null than WT mice. In addition to modest yet significant echocardiographic changes following acute CY-treatment, GSTP insufficiency was associated with greater phosphorylation of c-Jun and p38 as well as greater accumulation of albumin and protein-acrolein adducts in the heart. Mass spectrometric analysis revealed likely prominent modification of albumin, kallikrein-1-related peptidase, myoglobin and transgelin-2 by acrolein in the hearts of CY-treated mice. Treatment with acrolein (low dose, 1-5 mg/kg) also led to increased heart-to-body weight ratio and myocardial contractility changes. Acrolein induced similar hypotension in GSTP-null and WT mice. GSTP-null mice also were more susceptible than WT mice to mortality associated with high-dose acrolein (10-20 mg/kg). Collectively, these results suggest that CY cardiotoxicity is regulated, in part, by GSTP, which prevents CY toxicity by detoxifying acrolein. Thus, humans with low cardiac GSTP levels or polymorphic forms of GSTP with low acrolein-metabolizing capacity may be more sensitive to CY toxicity.
authors: Diabetes and Obesity Center, University of Louisville, Louisville, KY 40292, USA; Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292, USA. Electronic address: dj.conklin@louisville.edu.
authors: Daniel J
authors: DJ
authors: Conklin
authors: Diabetes and Obesity Center, University of Louisville, Louisville, KY 40292, USA; Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292, USA.
authors: Petra
authors: P
authors: Haberzettl
authors: Diabetes and Obesity Center, University of Louisville, Louisville, KY 40292, USA; Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292, USA.
authors: Ganapathy
authors: G
authors: Jagatheesan
authors: Diabetes and Obesity Center, University of Louisville, Louisville, KY 40292, USA; Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292, USA.
authors: Shahid
authors: S
authors: Baba
authors: Diabetes and Obesity Center, University of Louisville, Louisville, KY 40292, USA; Division of Nephrology, Department of Medicine, University of Louisville, Louisville, KY 40292, USA.
authors: Michael L
authors: ML
authors: Merchant
authors: Diabetes and Obesity Center, University of Louisville, Louisville, KY 40292, USA; Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, KY 40292, USA.
authors: Russell A
authors: RA
authors: Prough
authors: University of Cincinnati College of Medicine, Internal Medicine, Cincinnati, OH 45267, USA.
authors: Jessica D
authors: JD
authors: Williams
authors: Division of Cardiovascular Disease, University of Alabama-Birmingham, Birmingham, AL 35294, USA.
authors: Sumanth D
authors: SD
authors: Prabhu
authors: Diabetes and Obesity Center, University of Louisville, Louisville, KY 40292, USA; Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292, USA; Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, KY 40292, USA.
authors: Aruni
authors: A
authors: Bhatnagar
mesh_terms: D000171:Acrolein / Q000633:toxicity; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000633:toxicity*; D001794:Blood Pressure / Q000187:drug effects; D003520:Cyclophosphamide / Q000633:toxicity*; D004452:Echocardiography; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D006331:Heart Diseases / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology
chemical_list: D018906:Antineoplastic Agents, Alkylating; D000171:Acrolein; D003520:Cyclophosphamide; D005982:Glutathione Transferase; D020928:Mitogen-Activated Protein Kinases
keywords: Acrolein; Apoptosis; Cardiotoxicity; Cytoxan; GSTP1; JNK/c-Jun