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However, Cyclophosphamide is used in a high dose during the treatment, which has some side effects such as bone marrow suppression. Another side effect of high dose of CY may include acute cardiotoxicity which is characterized by endothelial damage followed by the release of toxic metabolites from the epithelial cells that can lead to the diastolic contractile dysfunction.
Cytochrome P450 is an enzyme that converts Cyclophosphamide into highly reactive metabolite Phosphoramide Mustard. Thus formed Phosphoramide Mustard causes DNA cross-links and induces cell death in proliferating cells. Other metabolic end products of the CY is acrolein which causes nephrotoxicity, urotoxicity as well as neurotoxicity. Acrolein is an unsaturated aldehyde compound that can react with Glutathione (cellular nucleophiles) and the side chain of some amino acid residues like Cysteine, Histidine present in the protein.
Glutathione-S-Transferase P is a member of Glutathione-S-Transferases that catalyzes the conjugation of acrolein, a degradation product of Cyclophosphamide with Glutathione and thus enhances the removal of acrolein. Though, there are many sources of acrolein that can reach to the body like through inhalation of acrolein, an increased level of acrolein in the urinary system in CY-treated patient suggested that acrolein is the one involved in Cyclophosphamide-induced cardiotoxicity.
Researchers took two types of mice; one with Glutathione-S-Transferase P-null (GSTP-/-) and another one wild-type (WT or GSTP+/+). To examine Cyclophosphamide-induced cardiotoxicity, researchers administered saline (for control) and varying the concentration of CY in mice. They also administered the varying amount of acrolein to mice to study if acrolein formation is involved in the cardiotoxicity induced by Cyclophosphamide or not.
After a specified period of time, the mice were killed and tissue levels of Glutathione and Thiobarbituric acid were measured in the stomach, kidney, heart, and liver. They also analyzed cardiotoxicity by measuring the level of Creatine Kinase-MB isoforms and the level of protein-acrolein adducts and they also performed echocardiography.
What they found is that mice treated with 300mg/kg CY led to a 2-fold increase in plasma CK levels in the wild-type of mice while, in the case of GSTP null mice, there was a > the 20-fold increase in plasma CK levels. This result reveals that GSTP null mice are more sensitive to the CY-induced toxicity than wild-type.
However, to know that Cyclophosphamide induces cardiotoxicity by forming acrolein, the level of protein adduct in the mice treated with acrolein was measured and found to be higher in GSTP null mice compared to the CY-treated GSTP null mice. The levels of GSTA, GSTM and Glutathione all were also measured and found to be same in both wild-type and GSTP null mice, indicating that it is GSTP which is affected by the Cyclophosphamide-induced cardiotoxicity.
In conclusion, Cyclophosphamide upon the action of Cytochrome P450 produces toxic metabolites like acrolein which causes cardiotoxicity by forming protein-acrolein adducts. However, it is the Glutathione-S-Transferase P which detoxifies the acrolein level by binding with and inactivating it.
Reference: Journal of Toxicology and Applied Pharmacology
Article doi: 10.1016/j.taap.2015.03.029