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Title: Glutathione S-transferase P protects against cyclophosphamide-induced cardiotoxicity in mice

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-dosemore » 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. - Graphical abstract: Cyclophosphamide (CY) treatment results in P450-mediated metabolic formation of phosphoramide mustard and acrolein (3-propenal). Acrolein is either metabolized and detoxified by glutathione S-transferase P (GSTP) via conjugation with GSH or acrolein can react with circulating and cardiac proteins to form protein–acrolein adducts that may contribute to cardiac injury, increased vascular permeability and edema and acute cardiotoxicity. Under low dose exposure, this event is reversible but at high levels of CY treatment and/or in susceptible individuals (e.g., hGSTP1 polymorphism), CY-induced cardiotoxicity is augmented and sudden death may occur. - Highlights: • Acute cardiotoxicity of cyclophosphamide (CY) is exacerbated in GSTP-null mice. • CY altered cardiac contractility, vascular leak and protein–acrolein adducts. • Cardiotoxicity of CY is recapitulated by acrolein only exposure. • Acrolein-induced cardiotoxicity and mortality is enhanced in male GSTP-null mice.« less
Authors:
 [1] ;  [2] ; ; ;  [1] ;  [2] ;  [1] ;  [2] ;  [1] ;  [2] ;  [3] ;  [4] ;  [1] ;  [2] ;  [2]
  1. Diabetes and Obesity Center, University of Louisville, Louisville, KY 40292 (United States)
  2. (United States)
  3. University of Cincinnati College of Medicine, Internal Medicine, Cincinnati, OH 45267 (United States)
  4. Division of Cardiovascular Disease, University of Alabama-Birmingham, Birmingham, AL 35294 (United States)
Publication Date:
OSTI Identifier:
22465767
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 285; Journal Issue: 2; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ACROLEIN; ALBUMINS; APOPTOSIS; BUILDUP; CREATINE; EDEMA; ENDOXAN; GLUTATHIONE; HEART; HEART FAILURE; HYPOTENSION; INJURIES; KALLIKREIN; MICE; MORTALITY; MYOGLOBIN; PHOSPHORYLATION; RADIATION DOSES; TOXICITY