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.

Altered ProteinS-Glutathionylation Identifies a Potential Mechanism of Resistance to Acetaminophen-Induced Hepatotoxicity

“…However, we could not find any direct evidence for negative regulation of JNK phosphorylation by GSTP in our studies; under basal (untreated) conditions, there was no difference in JNK phosphorylation between Gstp1 WT and Gstp1/2 2/2 mice (Fig. 3A), consistent with a number of studies in a range of other tissues or cells on different genetic backgrounds (Gate et al, 2004;Castro-Caldas et al, 2012;Bartolini et al, 2015;Conklin et al, 2015). JNK phosphorylates downstream transcription factors in response to a wide variety of stressors to induce apoptosis, cell proliferation, or differentiation.…”

Cardioprotective effects of Hypericum triquetrifolium Turra. against cyclophosphamide related cardiotoxicity in rats

“…This increase showed heart tissue damage, which are related with myocardial infarction, cardiac failure and myocarditis (Figure 2, 3). Similar to our study in many other studies [11,16,26] there was seen an increasing level of CK-MB when treated with CYP. Our biochemical data has been expressed in the same line with other studies which observed a significant increase in AST and CK-MB levels [25,29,32].…”

“…We may conclude that high-dose chemotherapy regimens together with using CYP may frequently associated with cardiotoxicity that could lead to myocyte devastation and congestive heart failure and CYP toxicity might be the result of increased permeability of cardiac mitochondrial membrane. As a matter of fact, this result has also been expressed by similar studies [16,26]. Overproduction of reactive oxygen species leads to the oxidative stress, DNA injury, cellular membrane impairment and necrosis in cells and tissues [27].…”

Glutathione s-transferase p in glucose homeostasis in mice.

“…Thus, enzymatic conjugation by GSTP facilitates and enhances the detoxification and removal of acrolein and other related aldehydes [52]. The physiological relevance of this metabolic proclivity is supported by studies in rodents that demonstrate a role for GSTP in protection against cardiovascular toxicity of direct acrolein exposure and acrolein-containing tobacco smoke as well as cyclophosphamide-induced urotoxicity and cardiotoxicity, and myocardial ischemia/reperfusion injury [59][60][61][62] . Among all the αβ-unsaturated aldehydes, acrolein is by far the strongest electrophile and reacts 100-fold more rapidly with thiols than 4-HNE [96,97] …”

“…GSTP-deficient (GSTPnull) did not show any obvious phenotype, although some null mice had higher body weights than controls [56]. Studies using GSTP-null mice have elucidated GSTP to be an important metabolic determinant of 7,12-dimethylbenz anthracene (DMBA)-induced carcinogenesis [56], APAP-induced hepatotoxicity [57], allergic airways disease [58], tobacco-induced endothelial dysfunction [59], cyclophosphamide-induced urinary bladder and cardio-toxicity [60] and more recently myocardial sensitivity to ischemia-reperfusion injury [61,62]. GSTP was also found to be a major GST isoform in the heart, lung and aorta and contributed significantly to total GST conjugating activity in those tissues.…”