Elsevier

Toxicology

Volume 143, Issue 3, 7 March 2000, Pages 219-226
Toxicology

The influence of thymoquinone on doxorubicin-induced hyperlipidemic nephropathy in rats

https://doi.org/10.1016/S0300-483X(99)00179-1Get rights and content

Abstract

The effect of thymoquinone (TQ), the main constituent of the volatile oil of Nigella sativa seeds, on the nephropathy and oxidative stress induced by doxorubicin (DOX) in rats was investigated. A single intravenous injection of DOX (6 mg/kg) induced a severe nephrotic syndrome (after 5 weeks) associated with hypoalbuminemia, hypoproteinemia, elevated serum urea, hyperlipidemia, and a high urinary excretion of protein, albumin and N-acetyl-β-d-glucosaminidase (NAG). In the kidney, DOX induced a significant increase in total triglycerides (TG), total cholesterol (TC), and lipid peroxides and a significant decrease in non-protein sulfhydryl (NPSH) content and catalase (CAT) activity. Treatment of rats with TQ (10 mg/kg per day) supplemented with the drinking water for 5 days before DOX, and daily thereafter, significantly lowered serum urea, TG, and TC. Similarly, TG, TC and lipid peroxides in the kidneys of TQ-treated rats were decreased significantly compared with DOX alone. Moreover, NPSH content and CAT activity in the kidneys of TQ-treated DOX group were significantly elevated compared with DOX alone. Treatment with TQ significantly suppressed DOX-induced proteinuria, albuminuria, and urinary excretion of NAG. The results confirm the involvement of free radicals in the pathogenesis of nephropathy induced by DOX. Likewise, the study demonstrates the high antioxidant potential of TQ and its marked effect on the suppression of DOX-induced nephropathy. The data suggest that TQ might be applicable as a protective agent for proteinuria and hyperlipidemia associated with nephrotic syndrome.

Introduction

Doxorubicin (DOX) is a potent cancer chemotherapeutic agent with efficacy in a broad range of malignancies (Blum and Carter, 1974). However, its clinical efficacy is limited because of severe cytotoxic side effects, the most serious being cardiotoxicity (Cortes et al., 1975). Also, renal injury has been reported to occur as a part of the toxic syndrome induced by DOX (O’Donnel et al., 1985). Intravenous (i.v.) administration of DOX in rats induces a nephrotic syndrome, which is characterized by proteinuria, albuminuria, hypoalbuminemia and hyperlipidemia (Desassis et al., 1997, Venkatesan et al., 1997). This experimental nephropathy resembles histologically and clinically minimal change nephropathy or focal and segmental glomerulosclerosis (Zima et al., 1997). There is an increasing evidence for the enhancing effect of free radicals involved in the primary pathogenic mechanism of DOX-induced nephropathy in rats (Bertani et al., 1986). Although various in vivo models of nephropathy induced by DOX have been described, there have been few animal studies carried out assessing compounds that may prevent DOX-induced nephrosis particularly proteinuria and hyperlipidemia (Montilla et al., 1997, Venkatesan et al., 1997).

The black seed of Nigella sativa Linn. family Ranunculaceae contains a fixed oil (>30%) and a volatile oil (0.40–0.45%). The volatile oil contains 18.4–24% thymoquinone (TQ) and many monoterpenes such as p-cymene and α-pinene (Aboutabl et al., 1986). Recently, TQ has been subjected to a range of pharmacological investigations. It has demonstrated an anti-inflammatory activity in rats (Mutabagani and El-Mahdy, 1997). Moreover, TQ was reported to inhibit eicosanoid generation in rat peritoneal leukocytes and ox brain membrane lipid peroxidation (Houghton et al., 1995). More recently, Nagi et al. (1999) indicated the ability of TQ and its metabolite, dihydrothymoquinone (DHTQ), to inhibit in vitro non-enzymatic lipid peroxidation in mouse liver. In our laboratory, TQ has been shown to attenuate a variety of renal toxicities that are the consequence of oxygen free radical damage, such as cisplatin-induced nephrotoxicity in rats and mice (Badary et al., 1997) and ifosfamide-induced Fanconi syndrome in rats (Badary, 1999). Similarly, TQ could protect against carbon tetrachloride-induced hepatotoxicity in mice (Al-Gharably et al., 1997) and DOX-induced cardiotoxicity in mice (Al-Shabanah et al., 1998). Therefore, the following study was conducted to determine whether supplementation with TQ in the drinking water ameliorates DOX-induced experimental hyperlipidemic nephropathy in rats. Nephropathy has been evaluated by measuring serum triglycerides (TG), total cholesterol (TC), urea, total protein, and albumin and urinary excretion of proteins, albumin, and N-acetyl-β-d-glucosaminidase (NAG). The antioxidant effect of TQ in the kidney was characterized by estimating the oxidative stress as indicated by lipid peroxide formation, non-protein sulfhydryl (NPSH) content and catalase (CAT) activity in renal tissue. It is confirmed here that TQ possesses an antioxidant-mediated protective role against DOX-induced nephrosis in rats.

Section snippets

Chemicals

DOX was used in the form of an injectable commercial product (Adriablastina, Farmitalia Carlo Erba, Milan, Italy). TQ [2-isopropyl-5-methyl-1,4-benzoquinone] was purchased from Sigma (St. Louis, MO). All other chemicals used were of analytical grade.

Animals

Male Wistar albino rats (bred in the animal unit), weighing 180–200 g at the start of the experiment, were used. They were housed in an animal facility that was maintained at 24±2°C and were allowed standard food (El-Nasr, Cairo, Egypt) and tap

DOX nephropathy

Treatment of rats with DOX produced the characteristic signs of a nephrotic syndrome including edema of the kidneys and liver, and fluid accumulation in the peritoneal cavity (data not shown). As shown in Table 1, rats with nephrosis showed a significant decline in body weight (33%), serum total protein (37%) and albumin (44%), elevation in serum urea (54%) and high excretion of protein (41-fold), albumin (30-fold) and NAG (66%) compared with saline-treated non-nephrotic rats. Nephrotic

Discussion

Recently, it was reported that TQ was effective in attenuating cisplatin-induced nephrotoxicity in rats and mice (Badary et al., 1997) and ifosfamide-induced Fanconi syndrome in rats (Badary, 1999). On the basis of previous findings, it was hypothesized that TQ might play an important role as an antiproteinuric agent in DOX model of nephrosis. Treatment with TQ produced a significant reduction in DOX-induced proteinuria and hyperlipidemia..

In the present study, the effect of TQ, supplemented

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