Abrogation of potassium bromate-induced renal oxidative stress and subsequent cell proliferation response by soy isoflavones in Wistar rats

Abstract

Potassium bromate (KBrO₃) is a potent nephrotoxic agent. In this study, we show the modulatory effect of soy isoflavones on KBrO₃-mediated renal oxidative stress and subsequent cell proliferation response in Wistar rats. KBrO₃ (125 mg/kg body weight, intraperitoneally) caused reduction in renal glutathione content, activities of renal anti-oxidant enzymes, viz., glutathione peroxidase, glutathione reductase, catalase, glucose-6-phosphate dehydrogenase and phase-II metabolising enzymes such as glutathione-S-transferase and quinone reductase with enhancement in xanthine oxidase, lipid peroxidation, γ-glutamyl transpeptidase and hydrogen peroxide (H₂O₂). KBrO₃ treatment also induced blood urea nitrogen, serum creatinine and tumor promotion markers, viz., ornithine decarboxylase (ODC) activity and thymidine [${}^3\text{H}$] incorporation into renal DNA. Treatment of rats orally with soy isoflavones (5 mg/kg body weight and 10 mg/kg body weight) resulted in a significant decrease in xanthine oxidase (P<0.05), lipid peroxidation, γ-glutamyl transpeptidase, H₂O₂ generation, blood urea nitrogen, serum creatinine, renal ODC activity and DNA synthesis (P<0.001). There was also significant recovery of renal glutathione content (P<0.01), anti-oxidant enzymes and phase-II metabolising enzymes (P<0.001). Thus, our results show that soy isoflavones acts as potent chemopreventive agent against KBrO₃-mediated renal oxidative stress, toxicity and subsequent cell proliferation response in Wistar rats.

Introduction

A disturbance in the pro-oxidant–anti-oxidant balance in favor of the former, leading to potential damage results in oxidative stress. It describes the steady state level of oxidative damage in a cell, tissue or organ caused by the reactive oxygen species (ROS). These ROS react with cellular membrane lipids, nucleic acids, proteins and enzymes resulting in cellular damage and degeneration. They are involved in the pathophysiology of many diseases including diabetes mellitus, Alzheimer’s disease, Parkinson’s disease, carcinogenesis, mutagenesis and ageing (Sun, 1990).

Potassium bromate (KBrO₃) is widely used as a food additive in the bread-making process for the maturation of flour because of its oxidizing properties and as a neutralizer in cold-wave hair lotions. It is also used in food products and in the production of fish paste and fermented beverages. It is also found in drinking-water samples as a by-product of ozone disinfection (Kurokawa et al., 1982). It has been demonstrated that KBrO₃ induces renal cell tumors, mesotheliomas of the peritoneum, and follicular cell tumors of the thyroid. KBrO₃ induces renal carcinogenesis and act as tumor promoter in carcinogen-initiated animals. Renal cell tumors have been observed in male and female rats after exposure of this compound (Kurokawa et al., 1990). It also enhances N-ethyl-N-hydroxyethyl-nitrosamine initiated renal tumors in rats (Umemura et al., 1995). There is enhancement in cellular proliferation in kidney due to oxidative stress generated by KBrO₃. It has also been reported that KBrO₃ cause DNA strand breaks and poly(ADPR) ribosylation in the kidney that is responsible for the proliferative response (Mc Laren et al., 1994). It has been reported to cause chromosomal aberrations and micronucleus formation both in vivo and in vitro (Kurokawa et al., 1990). It also induces 8-hydroxydeoxyguanosine (8-OH-dG), which is an oxidative DNA adduct and this suggests that it indirectly induce DNA modification by way of oxygen radicals and oxidative stress is involved in its carcinogenesis KBrO₃, is recognized as a useful marker of renal oxidative DNA damage as it also causes mutagenesis (Ballmaier and Epe, 1995).

Cancer prevention through identification of natural products that can block or slow down cancer development is an important area of cancer research. Recent studies from our lab have shown the chemopreventive effects of plants on chemically induced oxidative stress and cancer (Khan et al., 2001, Khan et al., 2003, Sultana et al., 2003).

Several constituents have been isolated from soy including isoflavones, phytosterols, protease inhibitors, inositol hexaphosphate, and saponins (Mazur et al., 1998). Isoflavones are one of the most promising agents found in soy for the treatment and prevention of osteoporosis, breast cancer, heart disease and the symptoms associated with menopause (Coward et al., 1993, Harbome, 1986). Isoflavones, sometimes referred to as phytoestrogens, are a group of phytochemicals that are found in soybeans. By mimicking human estrogen at certain sites in the body, isoflavones provide many health benefits that help to avoid disease. Isoflavones are found in soybeans, chickpeas and other legumes. However, soybeans are unique because they have the highest concentration of these powerful compounds.

The isoflavonoid fraction of soy consists primarily of genistein and diadzein, their 4′-methoxyl derivatives biochanin A and formononetin, glycetin and their corresponding glycosides genistin and diadzin (Fournier et al., 1998). Isoflavones possess anti-oxidant and phytoestrogenic properties. They have been shown to influence intracellular enzymes, protein synthesis, growth factor action, malignant cell proliferation, differentiation and angiogenesis (Messina and Barnes, 1991). Since soy isoflavones (Fig. 1) have protective effects in many diseases, we speculated that soy isoflavones might inhibit KBrO₃-induced nephrotoxicity. Therefore, in the present study, we assess the prophylactic treatment of rats with soy isoflavones on KBrO₃-induced renal oxidative stress and subsequent cell proliferation response.