Amelioration of cyclophosphamide-induced hepatotoxicity by the root extract of Decalepis hamiltonii in mice

Highlights

• The hepatoprotective potential of DHA against CP-induced liver damage.

• DHA prevented the elevation of serum marker enzymes in CP-treated mice.

• DHA enhanced the antioxidant defenses in the liver in vivo.

• DHA inhibited down-regulation of antioxidant enzymes gene expressions.

Abstract

Hepatoprotective potential of the aqueous extract of the roots of Decalepis hamiltonii (DHA) against cyclophosphamide (CP)-induced oxidative stress has been investigated in mice. Administration of CP (25 mg/kg b.w., i.p) for 10 days induced hepatic damage as indicated by the serum marker enzymes aspartate and alanine transaminases (AST, ALT), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH). Parallel to these changes CP induced oxidative stress in the liver as evident from the increased lipid peroxidation (LPO), reactive oxygen species (ROS), depletion of glutathione (GSH), and reduced activities of the antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione-S-transferase (GST). Treatment with DHA (50 and 100 mg/kg b.w., po) mitigated the CP-induced oxidative stress. Moreover, expression of genes for the antioxidant enzymes, were down-regulated by CP treatment which was reversed by DHA. Our study shows the DHA protected the liver from toxicity induced by CP and therefore, it could be serve as a safe medicinal supplement during cyclophosphamide chemotherapy.

Introduction

Therapeutic effectiveness of anticancer drugs is associated with severe side effects due to their toxicity. Cyclophosphamide (CP) is one of the widely used anticancer drugs for its therapeutic efficacy against a variety of cancers and disorders like systemic lupus erythematosus, rheumatoid arthritis and multiple sclerosis (Goldberg et al., 1986, Dollery, 1999, Perini et al., 2007). Earlier studies have shown that therapeutic dose of CP could cause liver toxicity (Shulman et al., 1980, Bacon and Rosenberg, 1982, Snover et al., 1989). CP undergoes a metabolic activation by hepatic microsomal cytochrome P450 mixed functional oxidase system to produce the two metabolites, phosphoramide mustard and acrolein, which are responsible for induction of oxidative stress (Sladek, 1971, Ludeman, 1999). Experimental evidence suggests that oxidative stress is responsible for cyclophosphamide hepatotoxicity (Stankiewicz et al., 2002, Manda and Bhatia, 2003, Selvakumar et al., 2005). In order to overcome the toxic side effect of anti-cancer drugs, some antioxidant agents are considered useful to alleviate oxidative stress. Accordingly a combination of treatment regimen with potent and safe antioxidants could be the desirable approach to mitigate CP-induced toxicity (Bhatia et al., 2008, Jalali et al., 2012). A number of studies have shown that plant extracts with antioxidant activity protect against CP hepatotoxicity (Sharma et al., 2000, Haque et al., 2001, Haque et al., 2003, Kumar and Kuttan, 2005, Sudharsan et al., 2005).

Decalepis hamiltonii (Wight and Arn.) (family: Asclepiadaceae), a climbing shrub, grows in the forests of peninsular India. Its tuberous roots are consumed as pickles and juice for its health promoting properties in southern India. The roots are also used in folk medicine and ayurvedic (the ancient Indian traditional system of medicine) preparations as a general vitaliser (Nayar et al., 1978). Our earlier work has shown that the roots of D. hamiltonii possess potent antioxidant properties (Harish et al., 2005). In our laboratory several novel antioxidant compounds have been isolated and characterized, which could be associated with their alleged health benefits (Srivastava et al., 2006a, Srivastava et al., 2006b, Srivastava et al., 2007). The root extract of D. hamiltonii also show hepatoprotective and neuroprotective potential in the laboratory rat (Srivastava and Shivanandappa, 2006, Srivastava and Shivanandappa, 2009, Srivastava and Shivanandappa, 2010a, Srivastava and Shivanandappa, 2010b). Therefore, D. hamiltonii aqueous extract (DHA) could be a good source of antioxidants from edible sources. In this study, we have investigated the ameliorative potential of DHA against CP-induced liver toxicity in the laboratory mouse.