Effects of lycopene against cisplatin-induced nephrotoxicity and oxidative stress in rats

Abstract

The aim of this study was to investigate the effects of lycopene on cisplatin-induced nephrotoxicity and oxidative stress in rats. Adult male Sprague–Dawley rats were randomly divided into four groups. The control group (group 1) received physiological saline; animals in group 2 received only cisplatin; a 10 days of lycopene pre-treatment was applied to the animals in group 3 before administration of cisplatin; a 5 days of lycopene treatment was performed following administration of cisplatin for the animals in group 4. Cisplatin (7 mg/kg) was intraperitoneally injected as a single dose and lycopene (4 mg/kg) was administered by gavage in corn oil. Biochemical and histopathological methods were utilised for evaluation of the nephrotoxicity. The concentrations of creatinine, urea, Na+ and K+ in plasma and levels of malondialdehyde and reduced glutathione as well as glutathione peroxidase and catalase activities were determined in kidney tissue. Administration of cisplatin to rats induced a marked renal failure, characterized with a significant increase in plasma creatinine and urea concentrations. Na⁺ and K⁺ levels of rats received cisplatin alone were not significantly different compared to control group, but they had higher kidney malondialdehyde, and lower reduce glutathione concentrations, glutathione peroxidase and catalase activities. Lycopene administration produced amelioration in biochemical indices of nephrotoxicity in both plasma and kidney tissues when compared to group 2; pre-treatment with lycopene being more effective. Results from this study indicate that the novel natural antioxidant lycopene might have protective effect against cisplatin-induced nephrotoxicity and oxidative stress in rat.

Introduction

Cisplatin (cis-diamminedichloroplatinum II, CP) is currently one of the most important cytostatic agents in treatment of a wide range of solid tumours. However, the clinical usefulness of this drug is limited by the development of nephrotoxicity, a side effect that may be produced in various animal models (Chirino et al., 2004, Greggi Antunes et al., 2000, Kim et al., 1997, Weijl et al., 2004). The xenobiotic-induced alterations in kidney functions are characterized by signs of injury, such as changes in urine volume, creatinine clearance, in glutathione (GSH) status, increase of lipid peroxidation (LPO). Formation of free radicals, leading to oxidative stress, has been shown to be one of the main pathogenic mechanisms of these toxicities and side effects of nephrotoxicants (Atessahin et al., 2003, Greggi Antunes et al., 2001). CP-induced nephrotoxicity is also closely associated with an increase in LPO in the kidney tissues. This antitumoural drug causes generation of reactive oxygen species (ROS), such as superoxide anion and hydroxyl radical, to deplete of GSH levels and to inhibit the activity of antioxidant enzymes in renal tissue. ROS may produce cellular injury and necrosis via several mechanisms including peroxidation of membrane lipids, protein denaturation and DNA damage (Kim et al., 1997, Mora et al., 2003).

Enzymatic and molecular defence mechanisms are present in the cell to prevent the integrity of biological membranes from oxidative processes caused by free radicals. The administration of antioxidants such as Vitamin E, Vitamin C, selenium and carotenoids, before or after treatment with CP has been used to protect or ameliorate against nephrotoxicity in human and animals (Giri et al., 1998, Martinis and Bianchi, 2001, Silva et al., 2001, Naziroglu et al., 2004).

Lycopene a naturally occurring carotenoid as tomatoes has attracted considerable attention as a potential chemopreventive agent. Recently, lycopene has received particular attention as a result of studies that have reported that it is a highly efficient antioxidant and has a singlet-oxygen and free radical scavenging capacity (Velmurugan et al., 2004, Tapiero et al., 2004, Cohen, 2002, Jonker et al., 2003, Michael McClain and Bausch, 2003). The aim of the present study was to evaluate the level of oxidative stress in CP-mediated nephrotoxicity and to investigate possible protective effect of lycopene on CP-induced renal damage in rats.