Elsevier

Toxicology

Volume 195, Issues 2–3, 15 February 2004, Pages 221-230
Toxicology

Selenium and high dose vitamin E administration protects cisplatin-induced oxidative damage to renal, liver and lens tissues in rats

https://doi.org/10.1016/j.tox.2003.10.012Get rights and content

Abstract

Cisplatin is one of the most active cytotoxic agents in the treatment of cancer but its clinical use is associated with nephrotoxicity. Several studies suggest that supplementation with antioxidant can influence cisplatin induced nephrotoxicity. In the present study, we investigated the effect of selenium with high dose vitamin E administration on lipid peroxidation (MDA) and scavenging enzyme activity in kidneys, liver and lens of cisplatin-induced toxicity in rats.

Forty female Wistar rats were used. They were randomly divided into five groups. The first and second groups were used as control and cisplatin (6 mg/kg BW) intraperitoneally administrated groups. Groups III, IV and V received intraperitoneally five doses of selenium (1.5 mg/kg BW) and a high dose of vitamin E (1000 mg/kg BW) combination before, simultaneously and after with cisplatin, respectively.

Glutathione peroxidase (GSH-Px), vitamin E and β-carotene levels in the kidney, lens and liver, vitamin A and reduced glutathione (GSH) levels in the kidney were significantly (P <0.05 to <0.001) lower in the cisplatin group than in the control whereas there was a significant increase in kidney, liver and lens MDA levels in rats treated with cisplatin. The decreased antioxidant enzymes and vitamins and increased MDA levels in the kidney, lens and liver of animals administered with cisplatin were significantly (P <0.05 to <0.001) improved with selenium and a high dose vitamin E injection.

In conclusion, this data demonstrates that there is an increase in lipid peroxidation in the kidney, liver and lens of animals administered with cisplatin whereas there is a decrease in antioxidant vitamins and enzymes. However, intraperitoneally injected selenium combined with a high dose of vitamin E seem to produce a significant improvement on antioxidants concentrations in rats treated before, simultaneously and after with cisplatin. The selenium with high dose vitamin E injection may play a role in preventing cisplatin-induced nephropathy and cataract formation in cancer patient.

Introduction

Cisplatin (Cis-diamminedichloroplatinum II) shows promise as an antitumor agent for several types of cancer and has been widely used for chemotherapy. Activity has been demonstrated against a variety of tumors, particularly for head and neck, testicular, ovarian, bladder and small cell lung cancers (Weijl et al., 1997, Kuhlmann et al., 1997). However, high-doses administered to patients produce nephrotoxic and hepatotoxicy side effects, and the dose of cisplatin must often be limited (Yoshida et al., 2000). The alterations in the kidney and liver functions induced by cisplatin are characterized by signs of injury, such as glutathione status, and cisplatin-induced nephropathy is closely associated with an increase in lipid peroxidation (Weijl et al., 1997, Antunes and Darin, 2000, Antunes et al., 2001, Mora et al., 2003).

The pathogenesis of renal damage caused by cisplatin is generally considered to be oxidative damage (Yoshida et al., 2000). Administration of cisplatin causes an increase in lipid peroxide (MDA) levels and a decrease in the activity of enzymes that prevent or protect against lipid peroxidation in the tissues. Therefore, the administration of antioxidants such as ebselen (Yoshida et al., 2000), vitamin C (Antunes and Darin, 2000) and selenium (Caffrey and Frenkel, 2000, Antunes et al., 2001) before treatment with cisplatin has been used to protect against nephrotoxicity in human and experimental animals. In the kidney, these treatments are reported to diminish the increase in MDA and the decrease in protective enzyme activity that are induced by cisplatin.

The selenium is an essential dietary trace element which plays an important role in a number of biological process (Combs and Combs, 1986). There is a long-standing association between selenium compounds and cancer chemo-prevention (Conklin, 2000). Many experimental studies in animals have demonstrated the ability of selenium to prevent carcinogenesis, and epidemiological studies have suggested that a decreased selenium status in humans is associated with an increased risk of cancer (Weijl et al., 1997). A recent widely publicized chemo-prevention study has shown that selenium supplements can decrease the incidence of certain types of cancer (Conklin, 2000). In addition, selenium in one study selenium (Caffrey and Frenkel, 2000) was utilized in preventing the nephrotoxic side effects of cisplatin although selenium in another selenium study (Antunes et al., 2001) had no effect.

The most frequently studied antioxidant vitamins are vitamins A and E. Vitamin A serves a prohormone for retroretinoids and intersects with signal transduction at cytoplasmic and membrane sites (Czernichow and Hercberg, 2001). Vitamin E is the major lipophilic chain-breaking antioxidant present within cell membranes (Packer and Landvik, 1990). In contrast to vitamins A and C, vitamin E can be safely used in high doses in the prevention of diseases such as diabetes and cardiovascular disease (Czernichow and Hercberg, 2001). It suppresses the oxidative stress of membranes. Given to potential role of the ROS in mediating tissue damage, cells contain The enzymes, superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), in the cells are important components of several naturally occurring antioxidant defense mechanisms to prevent oxidative injury (Weijl et al., 1997). There is also a hypothesis that decreased levels of natural antioxidants vitamins and diminished scavenging enzyme capacity may be responsible for the excess of ROS observed in cisplatin-induced toxicity (Weijl et al., 1997, Antunes and Darin, 2000, Antunes et al., 2001). Supplementation of the antioxidant vitamin C and selenium, has been reported to inhibit lipid peroxide in various conditions such as cisplatin-induced nephrotoxicity (Caffrey and Frenkel, 2000, Antunes and Darin, 2000).

If cisplatin increase MDA, increased amounts of enzymatic and non-enzymatic antioxidants should be oxidized and their levels in kidney, lens and liver should be diminished. To test this hypothesis, rats were studied after cisplatin administration to ascertain whether cisplatin in rats increases MDA and rate of kidney, liver and lens enzymatic and non-enzymatic antioxidants disappearance. The second aim of the current study was to test the effects of a moderate dose selenium and high dose vitamin E (SeVE) and its possible beneficial effect on antioxidant defense system by evaluating MDA and scavenging enzyme activity in rats administrated before or simultaneously or after with cisplatin. A combination of vitamin E with selenium was chosen since vitamin E, is a free radical scavenger (Weijl et al., 1997), and it was found, Antunes et al. (2001) informed that a selenium supplementation on its own did not have protective effects against cisplatin-induced toxicity.

Section snippets

Chemicals

All chemicals were obtained from Sigma Chemical Inc. (St. Louis, MO) and all organic solvents and sodium selenite from Merck Chemical Inc. (Darmstandt, Germany). The inject able form of vitamin E (dl-α-tocopheryl acetate) was obtained from F. Hoffman La Roche (Istanbul, Turkey). The inject able form of cisplatin was purchased from Eczacibasi (Istanbul, Turkey). All reagents were of analytical grade. All reagents except the phosphate buffers were prepared each day and stored in a refrigerator at

Changes in antioxidant enzyme and MDA levels and kidney weight

The changes in the MDA and GSH levels and GSH-Px activity in the kidney and lens were shown in Fig. 1, Fig. 2, Fig. 3. The MDA concentrations in the tissues were used as a measure of lipid peroxidation. When compared to control groups MDA levels in the kidney, liver, and lens were significantly (P<0.01) higher in groups administered with cisplatin. On the other hand, 5 days of SeVE administration was associated with a fall in the MDA levels of liver, lens and kidney. The effects of after

Discussion

Different strategies have been proposed to inhibit cisplatin-induced toxicity. Development of therapies to prevent the action of generation of free radicals may influence the progression of oxidative renal damage, along with the appearance of acute renal damage induced by cisplatin. Natural antioxidants such as vitamin E and selenium can be easily and safety increased in tissues by intraperitoneal supplementation since ideal way such as before, simultaneously and after with cisplatin is known.

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