Abstract 2951: Glutathione S-transferase P Deficiency Enhances Cardiovascular Sensitivity to Cyclophosphamide
The cardiotoxicity of anticancer drugs depends in part on individual variations in the metabolic capacity for drug activation and detoxification. In humans the glutathione S-transferase P (GSTP1–1) gene polymorphisms stratify risk of congestive heart failure in adults who were treated with anthracyclines for childhood leukemia. The GSTs catalyze the conjugation of glutathione (GSH) with electrophiles including anticancer drugs and their reactive metabolites. We tested the hypothesis that GSTP protects against cyclophosphamide-induced (CY) cardiotoxicity by detoxifying its metabolite acrolein. Male GSTP-null mice treated with CY (>200 mg CY/kg bwt) had significantly increased heart weight/bwt ratio, cardiac albumin content (~1.7-fold vs. control), increased plasma CK-MB level (control vs. CY, WT: 309±34 vs 491±32 U/L, n=6,6; GSTP-null: 338±44 vs. 2537±646 U/L, n=5,8; P<0.05) and cardiac protein-acrolein adducts (~100, ~80 and ~28 kDa bands by 1.8-, 2.8-, and 2-fold, respectively; P<0.05). These adducts were absent or diminished in CY-treated WT mice. Although cardiac p38 and ERK phosphorylation levels were similar between CY-treated WT and GSTP-null mice, CY-induced JNK phosphorylation was significantly greater in GSTP-null than in WT mice. Acrolein treatment (5 mg/kg) significantly depressed left ventricular ejection fraction (EF) and decreased the levels of reduced glutathione in the heart to a greater degree in GSTP-null mice than in WT mice (baseline vs. acrolein, WT: 0.73±0.02 vs. 0.66±0.04 EF, n=4; GSTP-null: 0.70±0.02 vs. 0.62±0.02 EF, n=4, P<0.05; [GSH] as % Control, WT: 127±7.3, n=8; GSTP-null: 81.3±5.8, n=8, P=0.07). Systemic CY- or acrolein- metabolism as measured by urinary hydroxypropyl mercapturic acid excretion was not different between WT and null mice. These findings suggest that GSTP protects against CY-induced cardiotoxicity via acrolein metabolism and detoxification in the heart, which prevents increased cardiac permeability, protein-acrolein adducts and JNK activation due to CY treatment. Because human GSTP polymorphisms code for protein variants that differ in catalytic efficiency, it is likely that GSTP1–1 polymorphisms directly influence the cardiotoxicity of CY and other anticancer drugs.