Abstract
Clinical application of cyclophosphamide (CP) as an anticancer drug is often limited due to its toxicity. CP is metabolized mainly in the liver by cytochrome P450 system into acrolein which is the proximate toxic metabolite. Many different natural antioxidants were found to alleviate the toxic effects of various toxic agents via different mechanisms. Therefore, the present study aimed at investigating the role of essential oils extracted from fennel, cumin and clove as natural antioxidants in the alleviation of hepatotoxicity induced by CP through assessment of hepatotoxicity biomarkers (AST, ALT, ALP), histopathology of liver tissues as well as other biochemical parameters involved in the metabolism of CP. The data of the present study showed that treatment of male mice with cyclophosphamide (2.5 mg/Kg BW) as repeated dose for 28 consecutive days was found to induce hepatotoxicity through the elevation in the activities of AST, ALT, and ALP. Combined administration of any of these oils with CP to mice partially normalized the altered hepatic biochemical markers caused by CP, whereas administration of fennel, clove or cumin essential oils alone couldn’t change liver function indices. Moreover, CP caused histological changes in livers of mice including swelling and dilation in sinusoidal space, inflammation in portal tract and hepatocytes, as well as, hyperplasia in Kuppfer cells. However, co-administration of any of the essential oils with CP alleviated to some extent the changes caused by CP but not as the normal liver. CP was also found to induce free radical levels (measured as thiobarbituric acid reactive substances) and inhibited the activities of superoxide dismutase, glutathione reductase, and catalase as well as activities and protein expressions of both glutathione S-transferase (GSTπ) and glutathione peroxidase. Essential oils restored changes in activities of antioxidant enzymes (SOD, CAT, GR, GST, and GPx) caused by CP to their normal levels compared to control group. In addition, treatment of mice with CP was found to induce the protein expression of CYP 3A4, 2B1/2, 2C6, 2C23. Moreover, the present study showed that essential oils reduced the expression of CYPs 2E1, 3A4 but could not restore the expression of CYP 2C6 and 2C23 compared to CP-treated mice. Interestingly, pretreatment of mice with essential oil of clove was found to restore activities of DMN-dI, AHH, and ECOD which were induced by CP to their normal control levels. It is concluded that EOs showed a marked hepatoprotective effect against hepatotoxicity induced by CP. In addition, co-administration of CP with any of these oils might be used as a new strategy for cancer treatment to alleviate the hepatotoxicity induced by CP.
Highlights
For more than 50 years cyclophosphamide (CP) has been widely used to treat various forms of cancers, including lymphoma, breast cancer and leukemia [1]
Compositional analysis of the extracted essential oils by Gas chromatography-Mass spectroscopy (GC-MS) demonstrated that eugenol (82.84%), acetyl eugenol (6.29%), β-caryophyllene (8.13%) and α-caryophyllene (1.05%) were the major chemical constituents of the hydrodistilled clove essential oil (Fig 1A, Table 1)
Administration of essential oils alone resulted in a favorable effect on hepatic antioxidant status, where they significantly increased the activity of endogenous antioxidant enzymes (GST, glutathione reductase (GR), glutathione peroxidase (GPx), Superoxide dismutase (SOD) and CAT) neither inducing lipid peroxidation nor depleting GSH levels
Summary
For more than 50 years cyclophosphamide (CP) has been widely used to treat various forms of cancers, including lymphoma, breast cancer and leukemia [1]. The toxic effects of CP are mainly due to the generation of two major metabolites namely phosphoramide mustard which is the antineoplastic moiety and acrolein metabolite which is the most toxic agent. These metabolites are generated by cytochrome P450 isozymes including CYP 3A4, 2B6, 2C9, and 2C19 [4]. Acrolein is a highly reactive α, β- unsaturated aldehyde, and was identified as the initiator of lipid peroxidation This reactivity is the main reason of the cytotoxicity in all cells exposed to acrolein [5] which limits using CP in clinical practice. CPinduced oxidative stress through the generation of free radicals leading to biochemical and physiological disturbances in animal models [6]
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