Abstract
The current study aimed to evaluate the protective effects of melatonin, a pineal secretory product, against hepatotoxicity induced by cyclophosphamide (CP) in mice. Mice were pretreated with melatonin intraperitoneally for 7 consecutive days before the administration of a single intraperitoneal dose of 200 mg/kg CP. 24 hr after CP administration, the mice were anesthetized, blood was then removed, and serum toxicity enzymes activities were evaluated. After the blood sampling, all animals were killed, livers were then removed, and histological studies were conducted. Serum toxicity marker enzymes were significantly increased after CP treatment but restored in melatonin pretreated groups. In addition, administration of CP induced necrotic hepatocyte with small crushed nuclei, portal space with severe inflammation, and hepatocytes surrounded by lymphocytic infiltration in hepatic tissues. However, melatonin effectively protected against CP-induced histopathological abnormalities in the liver tissues. Our results reveal that melatonin produces a potent hepatoprotective mechanism against CP. Therefore, melatonin could be a potent candidate to use concomitantly as a supplement agent against hepatotoxicity of CP for the patients undergoing chemotherapy.
Highlights
Cyclophosphamide (N,N-bis(2-chloroethyl)tetrahydro-2H1,3,2-oxazaphosphorin-2-amine 2-oxide, CP), an oxazaphosphorine derivative of the classical alkylating agent nitrogen mustard, is commonly used in cancer chemotherapy
We showed that melatonin had a potent chemoprotective effect against the genotoxicity induced by diazinon in human blood lymphocyte cells, and this protective effect might be the result of free radicalscavenging properties [16]
Serum alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP) activities were increased in all mice injected with CP relative to the untreated control animals (P < 0.001)
Summary
Cyclophosphamide (N,N-bis(2-chloroethyl)tetrahydro-2H1,3,2-oxazaphosphorin-2-amine 2-oxide, CP), an oxazaphosphorine derivative of the classical alkylating agent nitrogen mustard, is commonly used in cancer chemotherapy. This drug has significant immunosuppressive activity and is used clinically in the treatment of autoimmune diseases and for renal and bone marrow transplantations [1]. Phosphoramide mustard is believed to have an antineoplastic activity, while acrolein, a highly reactive metabolite with a short biological half-life, may be responsible for CPinduced liver injury [4]. Recent studies suggest that CP generates reactive oxygen species (ROS) like superoxide anion, hydroxyl radical, and hydrogen peroxide (H2O2) during its oxidative metabolism and depresses the antioxidant defense mechanisms in the liver [5, 6]. Regarding the above changes in the cells induced by CP, it is significant to find a compound capable of protecting the healthy cells and tissues against
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