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.