Phenolic extract of soybean (Glycine max) attenuates cisplatin-induced nephrotoxicity in rats

Abstract

The present study investigated the modulatory role of phenolic extract of soybean (PESB) in a rat model of nephrotoxic acute renal failure induced by cisplatin. Cisplatin (2 mg/kg/day) was administered to the rats for 5 days and the animals were pretreated with PESB (250–1000 mg/kg). Blood urea nitrogen reduced by 49.8% and 59.0%, serum creatinine by 34.7% and 62.1% and urinary N-acetyl-β-d-glucosaminidase also decreased by 37.7% and 49.2% following treatment with 250- and 500-mg/kg doses of the extract respectively in the cisplatin-treated rats. The extract also significantly increased renal myeloperoxidase activity by 26.8% and 40.6% at these doses. PESB also decreased renal xanthine oxidase activity and serum nitrate/nitrite in the cisplatin-treated rats. In addition, PESB significantly attenuated the marked renal oxidative damage that accompanied cisplatin treatment. The extract improved liver histology and significantly increased the activities of the antioxidant enzymes measured [superoxide dismutase, catalase, glutathione-S-transferase], prevented glutathione depletion and decreased malondialdehyde level following cisplatin treatment. Furthermore, cisplatin-induced decrease in the activities of glucose-6-phosphatase and 5′-nucleotidase in these rats was attenuated only at 250 mg/kg dose of the extract. We concluded therefore that PESB via antioxidant and possibly anti-inflammatory actions offered protective benefit against cisplatin-mediated acute toxic injury to the kidney.

Introduction

The mortality rate of patients with acute renal failure (ARF) has remained 25 to 75% despite the use of various pharmacological agents (Thadhani et al., 1996). Several therapeutic agents used in clinical practice have been reported to produce functional impairment and toxic injuries to the kidney and thus contribute a great deal to hospital acquired ARF and the development of nephropathy. The reason for this is not unconnected with the fact that the kidney is the major organ of excretion and as a result is exposed to large amount of parent and active metabolites of drugs and xenobiotics. It becomes imperative therefore that deliberate efforts are directed towards protecting the kidney from injuries and damage during therapies with agents that predispose to renal pathologies.

Cisplatin (cis-diamminedichloroplatinum II, CDDP) and other platinum derivatives are among the most effective chemotherapeutic agents widely used in the treatment of a variety of malignancies, including head and neck, ovarian and testicular cancers (Rabik and Dolan, 2007). However, the full clinical utility of these drugs (especially cisplatin) is limited by nephrotoxicity, the most common adverse effect, in many cancer patients (Schrier, 2002). Approximately 28 to 36% of patients receiving an initial dose (50–100 mg/m²) of cisplatin develop ARF (Lebwohl and Canetta, 1998, Ries and Klastersky, 1986). Since even vigorous hydration has not been effective in eliminating toxicity and the use of diuretics may complicate the electrolyte disturbance induced by cisplatin, discontinuation of cisplatin remains the only option in cases of progressive renal failure. Thus, there is a pressing need to protect the kidney while administering effective chemotherapeutic agents, such as cisplatin.

The mechanism of cisplatin nephrotoxicity remains to be fully elucidated. In addition to direct tubular toxicity in the form of apoptosis and necrosis (Arany and Safirstein, 2003), vascular factors (Luke et al., 1992, Winston and Safirstein, 1985) and inflammation (Ramesh and Reeves, 2002, Ramesh and Reeves, 2003) that have been implicated in the pathogenesis of cisplatin-mediated nephrotoxicity, several other studies have also demonstrated that oxidative stress is involved in the development of this drug’s renal tubule injury (Pabla and Dong, 2008, Chirino and Pedraza-Chaverri, 2009, Yilmaz et al., 2004, Kadikoylu et al., 2004). The involvement of oxidative stress is further supported by the fact that free radical scavengers and antioxidants prevented cisplatin-induced nephrotoxicity (Sener et al., 2000, Weijl et al., 2004, Satoh et al., 2003, Hara et al., 2001, Davis et al., 2001, Tsuruya et al., 2003, Dickey et al., 2005, Gulec et al., 2006).

There is increasing evidence that dietary phytoestrogens present primarily in soybeans as isoflavones have a beneficial role in chronic renal disease (Ranich et al., 2001). Nutritional intervention studies have shown that consumption of soy-based protein reduces proteinuria and attenuates renal functional or structural damage in animals and humans with various forms of chronic renal disease (Ranich et al., 2001). Having demonstrated the protective benefit of the phenolic extract of soybean (PESB) against renal injury induced by gentamicin (Ekor et al., 2006), we therefore hypothesized that the antioxidant polyphenolic compounds in soybean with demonstrable antitumor activity (Messina et al., 1994, Knight and Eden, 1996, Wei et al., 1995, Barnes et al., 1990) may provide the same protective benefit in cisplatin-mediated nephrotoxicity. To justify the rationale for this present investigation, we expressed the optimism that the anticarcinogenic effect of soybean may synergize with that of cisplatin while at the same time protecting the kidney from damage by the latter. If this happens, the therapeutic efficacy and clinical utility of cisplatin would be greatly enhanced.