Arch Toxicol (2007) 81:675–681 DOI 10.1007/s00204-007-0242-1
REVIEW ARTICLE
Renal deterioration caused by carcinogens as a consequence of free radical mediated tissue damage: a review of the protective action of melatonin Fatih Gultekin · Hicran Hicyilmaz
Received: 1 August 2007 / Accepted: 22 August 2007 / Published online: 7 September 2007 © Springer-Verlag 2007
Abstract This brief review summarizes some of the publications that document the preventive role of melatonin in kidney damage caused by carcinogens such as 2-nitropropane, arsenic, carbon tetrachloride, nitrilotriacetic acid and potassium bromate. Numerous chemicals generate excessive free radicals that eventually induce renal worsening. Melatonin partially or totally prevents free radical mediated tissue damages induced by many carcinogens. Protective actions of melatonin against the harmful eVects of carcinogens are believed to stem from its direct free radical scavenging and indirect antioxidant activities. Dietary or pharmacologically given melatonin may attenuate the oxidative stress, thereby mitigating the subsequent renal damage. Keywords Melatonin · Kidney · Free radical · 2-Nitropropane · Arsenic · Carbon tetrachloride · Nitrilotriacetic acid · Potassium bromate
Introduction In modern societies, being exposed to a multitude of harmful contaminants in the air, food or water has become inevitable. Many of these agents cause kidney damage and compromise renal function (Kim et al. 1998; Pal and Chatterjee 2005; Daniels et al. 1995; Qi et al. 1999; Karbownik et al. 2006). These toxins have a variety of
F. Gultekin (&) · H. Hicyilmaz School of Medicine, Department of Biochemistry, Suleyman Demirel University, Tip Fakultesi, Biyokimya AD, 32260 Isparta, Turkey e-mail:
[email protected];
[email protected]
means that eventually induce their harmful eVects. The current survey focuses on the free radical processes that lead to molecular mutilation. Numerous carcinogens including 2nitropropane (2-NP) (Kim et al. 1998), arsenic (Pal and Chatterjee 2005), beryllium (Johri et al. 2004), carbon tetrachloride (CCl4) (Daniels et al. 1995), chromium (Bagchi et al. 2002), ferric nitrilotriacetate (Qi et al. 1999), and potassium bromate (Karbownik et al. 2006) as well as some other chemicals including naphthalene (Omurtag et al. 2005), stannous chloride (El-Demerdash et al. 2005), benzene (Rana and Verma 2005), Xuoride (Arhima et al. 2004), sulWte (Vincent et al. 2004), toluene (Al-Ghamdi et al. 2003), and ethylene glycol (Huang et al. 2002) generate excessive free radicals that eventually induce renal damage. Plenty of experimental evidence supports the view that reactive oxygen species (ROS) play a key role in the pathophysiologic processes of renal diseases (Rodrigo and Rivera 2002). The cellular damage is mediated by an alteration in the antioxidant status, which increases the concentration of ROS. The abundance of polyunsaturated fatty acids (PUFA) makes the kidney particularly vulnerable to ROS attack (Kubo et al. 1997). Oxidative stress mediates a wide range of renal impairments, from acute renal failure (Nath and Norby 2000), drug toxicity (Basivireddy et al. 2004), diabetic nephropathy (Winiarska et al. 2004), obstructive nephropathy (Klahr 2001), hyperlipidemia (Scheuer et al. 2000), and glomerular damage (MorenoManzano et al. 2000) to chronic renal failure and hemodialysis (Sener et al. 2004; Kan et al. 2002). Melatonin (N-acetyl 5-methoxytryptamine), the main secretory product of the pineal gland, and its metabolites have been shown to fortify the antioxidant system by scavenging free radicals (Reiter et al. 2003a, b; Tan et al. 2007), stimulating antioxidant enzymes (Reiter et al. 2000) and the synthesis of glutathione (GSH, an essential intracellular
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antioxidant) (Urata et al. 1999), increasing the activities of other antioxidants (Gitto et al. 2001), protecting antioxidative enzymes from oxidative damage (Mayo et al. 2003), and augmenting the eYciency of the mitochondrial electron transport chain by means of that lowering electron leakage and reducing free radical generation (Acuna et al. 2002). Melatonin as a powerful antioxidant can easily cross cell membranes and the blood-brain barrier. Unlike other antioxidants, melatonin does not undergo redox cycling, the ability of a molecule to undergo reduction and oxidation repeatedly. Redox cycling may allow other antioxidants (such as vitamin C) to act as pro-oxidants, counterintuitively promoting free radical formation. Melatonin, once oxidized, cannot be reduced to its former state because it forms several stable end-products upon reacting with free radicals. Therefore, it has been referred to as a terminal (or suicidal) antioxidant (Tan et al. 2000). Melatonin, by reducing oxidative stress, has been reported to reduce in vivo and in vitro tissue damage due to free radical generation (Reiter et al. 2003a, b). The mechanism of the antioxidant eVects of melatonin has been summarized in Fig. 1. Herein, we summarize the data that illustrate the protective action of melatonin against the following toxic agents.
2-Nitropropane The secondary nitroalkane, 2-NP, is widely used as an intermediate in chemical synthesis and in the formulation
Fig. 1 A summary of the actions of melatonin in attenuating oxidant generation and reducing oxidative damage. ·OH: hydroxyl radical, H2O2: hydrogen peroxide, O2·¡: superoxide anion radical, 1O2: singlet oxygen, NO·: nitric oxide, ONOO¡: peroxynitrite anion, HOCl: hypochlorous acid, c3-OHM: cyclic 3-hydroxymelatonin, AFMK: N1acetyl-N2-formyl-5-methoxykynuramine, AMK: N1-acetyl-5-methoxykynuramine, SOD: superoxide dismutase, GSH-Px: glutathione peroxidase, CAT: catalase, GSH-Rd: glutathione reductase, NOS: nitric oxidase synthase, GSH: Glutathione
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of inks, paints, varnishes, adhesives and other coatings (IARC 1982); it is also found in cigarette smoke (HoVmann and Rathkamp 1968). This compound is known to be a potent hepatocarcinogen (Kim et al. 1998). Recent studies suggest that 2-NP generates ROS, which may account for the carcinogenic eVects of this molecule (Kohl et al. 1995; Kohl and Gescher 1997). 2-Nitropropane given to rats at the doses of 1, 2, 3 or 4 mmol/kg body weight (i.p.) and observed causes gradual increments in lipid peroxidation (LPO) products, malondialdehyde (MDA) and 4-hydroxyalkenals (4-HDA), with increasing doses of 2-NP (Kim et al. 1998). Increased LPO in kidney indicates that 2-NP is a potent nephrotoxin. When melatonin administered at doses of 2.5, 5.0 and 10.0 mg/kg 30 min prior to 4 mmol/kg 2-NP, it reduced LPO levels in kidney tissue (Figs. 2, 3). The mechanism by which 2-NP causes renal toxicity is poorly understood and has been studied primarily at the level of nucleic acids. 2-NP forms of a variety of intermediate metabolites including the anionic tautomer propane 2nitrate (Kohl et al. 1994), nitric oxide (NO·) (Kohl et al. 1995), the lipid hydroperoxide radical (ROO·), and the nitrogen dioxide radical (Bors et al. 1993). These metabolites, either directly or indirectly after their subsequent metabolism, presumably account for the induction of DNA damage. Since some of the intermediates are free radicals it is presumed that these are involved in the processes that inXict damage at the level of the kidney. Given melatonin’s marked antioxidant activities (Reiter et al. 2003a, b), melatonin and/or its metabolites may reduce the toxic eVects of 2-NP as a consequence of its ability to directly scavenge the toxic reactants or due to its ability to induce enzymes, which metabolize the intermediates to innocuous products.
Fig. 2 The levels of lipid peroxidation (LPO) products [malondialdehyde (MDA) and 4-hydroxyalkenals (4-HDA)] in rat kidney tissue with time after injection of 4 mmol/kg 2-nitropropane (2-NP). Values are means § SEM (N = 6). Point marked with an asterisk is signiWcantly higher than 0-time value at P < 0.0001
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Fig. 3 The suppressive eVect of melatonin at increasing doses on MDA and 4-HDA levels in kidney tissue of rats treated with 4 mmol/ kg 2-NP 24 h previously. Melatonin was given 30 min before the 2-NP injection, and each parameter was analyzed after 24 h. Values are means § SEM (N = 6). Points marked with an asterisk are signiWcantly lower than values of the 2-NP group alone with a P < 0.05
Arsenic Arsenic, a potent environmental toxin, has a number of harmful eVects in humans. Among other negative eVects, arsenic is a carcinogen (Wang and Huang 1994). Cellular mechanisms of arsenic toxicity involve the generation of ROS (Chen et al. 1998). ROS produced as a consequence of arsenic ingestion is involved in its genotoxicity (Jha et al. 1992), tissue degenerative changes (Prasad and Rossi 1995) and instability of the cytoskeletal structure (Li and Chou 1992). Enhanced generation of ROS after arsenic exposure alters the intrinsic antioxidant defenses of cells resulting in elevated levels of oxidative stress (Ercal et al. 2001). Numerous studies (Gupta et al. 2007; Mittal and Flora 2006) reported increased LPO in kidney by arsenic exposure. However, Pal and Chatterjee (2006) showed that arsenic treatment (i.p.) at a dose of 5.55 mg/kg body weight for a period of 30 days decreased LPO in kidney. In this study, arsenic caused changes in the antioxidant system such as decreasing the activities of superoxide dismutase (SOD) and catalase (CAT), and increasing the level of GSH and free hydroxyl radical, and glutathione reductase (GR) activity. Melatonin supplementation (i.p.) at a dose of 10 mg/kg/day for the last 5 days prior to tissue collection restored all parameters near to control values except CAT. In addition, there are several reports of altered carbohydrate metabolism during arsenic intoxication (Reichl et al. 1988; Boquist et al. 1988). Pal and Chatterjee (2005) reported arsenic treatment (i.p.) at a dose of 5.55 mg/kg body weight for 30 days enhanced mobilization of free
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amino acids from the kidney to the liver; in this study, melatonin supplementation (i.p.) at a dose of 10 mg/kg/day for last 5 days prior to sacriWcing restored both liver and kidney free amino acid nitrogen concentrations. This study also reported that a reduction in glutamate–pyruvate transaminase (GPT) activity in the kidney of rats following arsenic treatment with this response being prevented if the animals were also given melatonin. Arsenic alters nuclear binding levels of the transcription factors activator protein-1 (AP-1) and nuclear factor-kappa (NF-) to their respective cis-acting elements (Kaltreider et al. 1999). Arsenic is also known to inhibit poly ADP-ribosylation, which is implicated in DNA repair, signal transduction and apoptosis (Ramanathan et al. 2005). Ramanathan et al. (Jou et al. 2004) found that tumor necrosis factor- (TNF-), which triggers activation of caspase3, is a major pathway that initiates apoptosis in arsenicexposed rats. In this study, they also showed that vitamins C and E inhibited free radical mediated apoptosis due to their scavenging activities. Melatonin is known to reduce the translocation of NF- into the nucleus and binding to DNA (Jou et al. 2004). Via this action and due to its free radical scavenging activities, melatonin has potent antiapoptotic actions (Chuang et al. 1996), which very likely contributed to its ability to reduce renal damage that is a result of arsenic exposure.
Carbon tetrachloride Carbon tetrachloride (CCl4) is a notorious environmental biohazard. It occurs in drinking water and is frequently used as a solvent, cleansing agent, and herbicide. CCl4 is particularly toxic to the liver, where it characteristically causes the accumulation of fatty acids leading to hepatocellular degeneration and centrolobular necrosis (Kim et al. 1990; Valles et al. 1994). CCl4 also impairs enzymatic systems as evidenced by decreases in the activities of aminopyrine desmethylase, cytochrome p450 and glucose-6phosphatase (Daniels et al. 1995). The generation of free radicals appears to be pivotal in CCl4 hepatotoxicity. CCl4 is metabolized by cytochrome p450 to produce the trichloromethyl radical, which initiates a cascade of free radical reactions resulting in LPO and a reduction in the activities of a number of enzymes (Recknagel et al. 1989). In addition to the hepatic changes, an elevation of lipid hydroperoxides (LOOH) levels in kidney of mice after a single dose of CCl4 (0.25 ml/g) has been reported (Weyers et al. 2001). Daniels et al. (1995) treated rats with CCl4 (5 ml/kg, i.p.) 3 h before the animals were killed and found high levels of LPO products (MDA and 4-HDA) in kidney tissues. When CCl4 treatment was combined with melatonin (10 mg/kg, i.p.), given 30 min before and 60 min after
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the administration of CCl4, the signiWcantly elevated levels of renal LPO products induced by CCl4 were nearly completely prevented (Fig. 4). The authors speculated that given the evidence of a reduction in oxidative stress in the kidneys of animals treated with both CCl4 and melatonin, the indoleamine was protective as a consequence of its ability to neutralize free radicals and radical intermediates resulting from the metabolism of CCl4.
Nitrilotriacetic acid Nitrilotriacetic acid (NTA) is a synthetic aminotricarboxylic acid, which forms water-soluble chelate complexes with several metal cations including iron at a neutral pH. It is widely used as a substitute for polyphosphates in detergents for household and hospital use (Anderson et al. 1985). The uncomplexed NTA has low toxicity in experimental animals (Hamazaki et al. 1985), but the ferric chelate of NTA (Fe-NTA) has been reported to induce acute and subacute renal proximal tubular necrosis and a subsequent high incidence (60–92%) of renal adenocarcinoma in both rats and mice (Okada and Midorikawa 1982). Additionally, other reports have shown that Fe-NTA induces elevated concentrations of LPO products [thiobarbituric acid-reactive substances (TBARS), MDA, hydroxynonenal (HNE) and HNE-modiWed proteins], oxidative DNA damage as indicated by rises in 8-hydroxydeoxyguanosine (8-OHdG), depletion of GSH as well as all major antioxidant enzymes in the rat kidney (Iqbal et al. 2003a, b).
Fig. 4 The eVects of melatonin (MEL: 10 mg/kg, i.p.) pretreatment on MDA plus 4-HAD concentrations in kidneys of carbon tetrachloride (CCl4: 5 mg/kg, i.p.) treated rats. Values are the means § SEM of 6–10 animals. *SigniWcantly diVerent from CCl4-treated group, P < 0.005
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Qi et al. (1999) reported that treatment rats with Fe-NTA (15 mg Fe/kg, i.p.) resulted in a signiWcant increase in the levels of LPO products (MDA + 4-HDA) and in the oxidative DNA damage marker, 8-OHdG, 1 h after its administration. Pretreatment with melatonin (25 or 50 mg/kg) 30 min before the Fe-NTA injection prevented the rises in the levels of LPO products and 8-OHdG induced by FeNTA in the rat kidney (Figs. 5, 6). The auto-oxidation of Fe2+-NTA generates superoxide radicals (O2·¡) which subsequently potentiate the iron-catalyzed Haber–Weiss reaction to produce hydroxyl radicals (·OH), a radical that readily oxidizes lipids and DNA (Umemura et al. 1990). Chelation of Fe2+ by NTA enhances auto-oxidation (Hamazaki et al. 1989). Melatonin neutralizes ·OH by directly scavenging it and indirectly by metabolizing its precursor, H2O2, to non-toxic products
Fig. 5 EVect of melatonin on kidney LPO in Fe-NTA (Ferric chelate of nitrilotriacetic acid) injected rats. Results are given as mean § SEM (n = 6). *P < 0.05 compared with Fe-NTA group. Mel (25) = 25 mg/ kg melatonin; Mel (50) = 50 mg/kg melatonin. The concentration of Fe-NTA was 15 mg Fe/kg body weight
Fig. 6 Inhibitory eVect of melatonin on Fe-NTA (15 mg/kg)-induced levels of 8-OH-dG in rat kidney. Results are given as mean § SEM (n = 6). *P < 0.05 compared with Fe-NTA group. Mel (25) = 25 mg/ kg melatonin; Mel (50) = 50 mg/kg melatonin
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(Reiter et al. 2003a, b). Besides these actions, Limson et al. (1998) found that melatonin has a high metal-binding aYnity. In their study, melatonin was shown to bind Fe3+, thus preventing it from being reduced back to Fe2+, which promotes the formation of the ·OH via the Fenton reaction. Removal of Fe3+ by melatonin would thus further reduce ·OH generation. Presumably each of these features of melatonin would assist this molecule in reducing Fe-NTA-mediated oxidative damage in the kidney.
Potassium bromate Potassium bromate (KBrO3) is classiWed as a group 2B carcinogen (a possible human carcinogen) (IARC 1986). KBrO3 had been used as a food additive in Xour and barley processing and as a component in cold-wave hair lotions. In 1992, the approval for its use in the treatment of Xour was withdrawn (JECFA 1992). However, there is still some concern, because of the presence of KBrO3 in the environment. Bromate is an inorganic oxyhalide by-product formed during water disinfection by ozonation, and therefore it is frequently detected in tap and bottled water (van Dijk-Looijaard and van Genderen 2000). KBrO3 has been demonstrated to experimentally induce renal tumors in rats (Kurokawa et al. 1990). Although the mechanism of KBrO3 genotoxicity is not known, it has been suggested that ROS might contribute to its renal carcinogenicity (Sai et al. 1994). This compound has been shown to cause oxidative modiWcation of DNA bases, lipids and proteins in the kidney (Karbownik et al. 2006). Additionally, KBrO3 is known to decrease the activity of an important antioxidative enzyme, glutathione peroxidase and increase the formation of the following free radicals and ROS: superoxide anion radical (O2·¡), nitric oxide (NO·), and the peroxynitrite anion (ONOO ¡) (Watanabe et al. 2002). KBrO3, when injected into rats, signiWcantly increased LPO levels measured in the kidneys. Co-treatment with melatonin reduced KBrO 3-induced oxidative damage to lipids in the rat kidneys (Karbownik et al. 2006; ElSokkary 2000) (Fig. 7). Cadenas and Barja (1999) showed that level of 8-OHdG in the renal genomic DNA signiWcantly increased by more than 100% after KBrO3 treatment. This increase was partially prevented by melatonin (Table 1). KBrO3 also caused histopathological changes in kidney including atypical tubular structure, hyperplasia, hyaline droplet degeneration, necrotic changes and stratiWed squamous cell metaplasia. With regard to these changes, melatonin treatment also inhibited this tissue damage associated with KBrO3 administration (El-Sokkary 2000).
Fig. 7 Concentrations of MDA + 4-HDA in the homogenates of kidneys, collected from the rats, administered 0.9% NaCl:ethanol (Control; n = 9), or KBrO3 (n = 9), or melatonin (n = 8), or KBrO3 + melatonin (n = 8). Data are expressed as nmol of MDA + 4-HDA per mg protein. Bars represent the means § SEM. *P < 0.05 versus Control. **P < 0.05 versus KBrO3
Table 1 Oxo8dG renal concentration in rats treated with melatonin and KBrO3 (80 mg/kg) 6 h before being killed Groups
Oxo8dG/105dG
Control
1.8 § 0.11
KBrO3
4.0 § 0.46a
KBrO3 + melatonin
3.0 § 0.30b,c
Values are mean § SEM from Wve rats a SigniWcantly diVerent from control group, P < 0.001 b SigniWcantly diVerent from control group, P < 0.01 c SigniWcantly diVerent from KBrO3 group, P < 0.05
Concluding remarks A great number of carcinogens have been found to cause ROS in kidney tissue resulting in free radical damages. Melatonin has been shown to prevent fully or partially free radical mediated tissue damages caused by the carcinogens 2-NP, arsenic, CCl4, NTA and KBrO3. Possibly, melatonin exerts these protective eVects mainly its direct or indirect antioxidant properties. Therefore, dietary or pharmacologically given melatonin, favoring the scavenging and/or depuration of ROS, may attenuate or prevent the oxidative stress, thereby mitigating the subsequent renal damage.
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