Effect of melatonin, curcumin, quercetin, and resveratrol on acute ferric nitrilotriacetate (Fe-NTA)-induced renal oxidative damage in rats.

The influence of melatonin, curcumin, quercetin, and resveratrol pretreatment on ferric nitrilotriacetate (Fe-NTA)-induced oxidative renal damage was studied. Male Wistar rats were treated orally once daily for 3 days with melatonin (10 mg/kg), curcumin (50 mg/kg), quercetin (15 mg/kg), and resveratrol (10 mg/kg). One hour after the last dose of antioxidants, a single dose of Fe-NTA was administered (8 mg of Fe/kg body weight, i.p.) to pre-treated animals. Twenty-four hours after Fe-NTA administration, the lipid peroxidation (LP), reduced glutathione (GSH), catalase (CAT), and glutathione peroxidase (GSH-Px) were estimated in kidney homogenates. Iron, zinc, and copper concentrations were estimated in kidney tissue. Administration of Fe-NTA to rats induced renal LP (170%, P < 0.001) and inhibited catalase (78%, P < 0.05) in the kidney. The oral pretreatment with melatonin, curcumin, quercetin, and resveratrol each one was effective in decreasing the Fe-NTA-induced LP (P < 0.001); however, it did not influence the FeNTA-induced inhibition of renal CAT activity. No changes were found in renal GSH level and GSH-Px activity compared to control animals. The pretreatment with antioxidants did not affect the increase in renal iron content, blood urea nitrogen/creatinine ratio, and relative kidney weight of FeNTA-intoxicated rats. The results indicate that the pretreatment with natural antioxidants, curcumin, melatonin, quercetin, and resveratrol, significantly and equally suppressed lipid peroxidation induced by Fe-NTA but had no effect on other markers of FeNTA nephrotoxicity and iron deposition in kidneys.

The effect of estradiol on the oxidative damage and trace element level determined in the liver of rats treated with dimethylarsinic acid.

DMA--dimethylarsinic acid (cacodylic acid)--used as an herbicide, is the major metabolite formed after the exposure to inorganic arsenics in mammals. It is considered to have an important role in arsenic carcinogenesis through the induction of oxidative damage in various tissues. Estradiol, apart from its main hormonal effect, displays both prooxidative and antioxidative action depending on the condition of the treatment. The oxidative stress plays a crucial role in estrogen-induced carcinogenesis. In the experiments performed in female Wistar rats receiving drinking water ad libitum with 0.01% DMA for 10 weeks, one half of rats was treated with 17beta-estradiol (0.1 mg/rat s.c., twice a week) starting the 3rd week. One more group received estradiol only and last group served as controls receiving drinking water without treatment. The DMA enhanced lipid peroxidation in the liver, estradiol treatment potentiated this effect of arsenic. The GSH level was enhanced in DMA+estradiol treated group. In estradiol-only treated group both the lipid peroxidation and GSH content were increased. The administration of estradiol caused an enhancement of several trace element concentrations in the liver, mainly that of iron and copper. The critical role of estrogen on the development of oxidative stress was thus proved.

Effects of kojic acid on oxidative damage and on iron and trace element level in iron-overloaded mice and rats.

Since members of hydroxypyrone series posses iron chelating properties, kojic acid (KA), 5-hydroxy-2-(hydroxymethyl)-4H-pyran-one, a fungal metabolite of natural origin, has been suggested to might play a role in iron-overload diseases and in oxidative stress conditions involving transition metal. In our experiments in vivo models of iron-overload were used to study iron-chelating properties of KA and its effect on oxidative damage in mice and rats. The treatment of iron-preloaded rats (25 mg Fe x kg(-1) b.w., i.p., daily for five days) with 0.5% KA in drinking water for four weeks did not lower the iron concentration accumulated in the liver, neither diminished the induced hepatic lipid peroxidation in iron-loaded rats. The GSH level decreased in KA-treated group. Similarly, in iron-loaded mice model experiment, the following oral treatment with KA (100 mg x kg(-1)) daily for 7 days did not decrease the level of Fe accumulated in the liver and the lipid peroxidation even enhanced after KA treatment. Though in our experiments in vivo the ability of kojic acid to affect iron kinetics in the organism could not be proved, kojic acid as a molecule of natural origin may serve as a template for the preparation of new biologically active derivatives possessing capability of chelating iron.

The influence of alpha-lipoic acid on the toxicity of cadmium.

Alpha-lipoic acid (alpha-LA) is an important antioxidant drug with chelating properties. In experiments performed in male mice (CD-1, Charles River) the effects of cadmium on lipid peroxidation (LP), GSH level, the activity of catalase and glutathione peroxidase (GSH-Px) in liver homogenates were studied. Mice were injected with CdCl2 x 2.5 H2O at a dose of 40 micromol x kg(-1) s.c. Alpha-LA was administered simultaneously i.p. at the dose corresponding to alpha-LA-to-Cd molar ratio of 5:1. The experiments were completed at 24 h. Cadmium increased LP to 200.7% of controls. This effect was prevented by alpha-LA treatment (p < or = 0.05). GSH level was decreased to 81.7% of controls and it was not affected by alpha-LA. GSH-Px activity diminished by Cd administration was corrected by alpha-LA (p < 0.001). Catalase activity decreased by Cd remained unaffected. The administration of alpha-LA alone enhanced LP and the activity of catalase. As estimated by AAS, Cd content in the liver, the kidneys, the brain and the testes remained unaffected by alpha-LA treatment. In the acute toxicity experiment, the mortality associated with cadmium was decreased by alpha-LA administration. The results suggest that the toxicity of Cd was decreased mainly by the antioxidant activity of alpha-LA rather than by cadmium removal from tissues.

Effect of cadmium chelating agents on organ cadmium and trace element levels in mice.

In experiments performed on male mice (CD-1, Charles River), the mobilizing effects of repeated administration of the carbodithioate analogue BLDTC [N-benzyl-4-O-(beta-D-galactopyranosyl)-D-glucamine-N-carbodithioate+ ++] and CaDTPA (calcium trisodium pentetate) on cadmium deposits in the liver, kidneys, brain and testes were compared. The antidotes were injected alternately every 48 h over a period of 16 d (8 doses in total) following a previous loading with 20 doses of CdCl2.2.5 H2O (single doses of 3 mg kg-1 i.p.). The experiments confirmed BLDTC to be one of the most effective cadmium mobilizing agents. The administration of CaDTPA, which is known as a useful antidote in acute cadmium intoxication, increased the mobilizing effect of BLDTC. Cadmium elevated the concentration of zinc in all organs examined and the level of copper in the liver, kidneys and testes. This accumulation of trace elements was only partially corrected by the chelators. The antidotes administered alone exert only a negligible effect on the trace element levels in the organs.

Effect of chelators, monoisoamyl meso-2,3-dimercaptosuccinate and N-(4-methylbenzyl)-4-O-(beta-D-galactopyranosyl)-D-glucamine-N-carbodit hioate, on cadmium and essential element levels in mice.

In experiments performed on male mice (ICR) the mobilizing effect of monoisoamyl meso-2,3-dimercaptosuccinate (Mi-ADMS) and a dithiocarbamate analogue, N-(4-methylbenzyl)-4-O-(beta-D-galactopyranosyl)-D-glucamine-N-carbod ithioate (MeBLDTC) on the cadmium deposits was studied. The influence of these compounds on the changes in the level of essential elements caused by cadmium was explored. CdCl2.H2O was injected intravenously. The chelators were administered every 48 h over 12 d. Both compounds are effective in mobilizing cadmium from the body in animal experiments. On an equimolar basis MeBLDTC was superior to Mi-ADMS. Mi-ADMS can, however, be administered orally. Both compounds were able to correct, at least partly, the changes in the level of essential elements caused by cadmium.

[Protective effect of sho-saiko-to (TJ 9) in experimental liver injury]. / K ochrannému úcinku prípravku sho-saiko-to (TJ 9) pri experimentálním poskození jater.

Experiments carried out on male mice (ICR) demonstrated a protective effect of premedication with the preparation Sho-Saiko-To (TJ 9, Tsumura and Comp.) against the hepatotoxic effects of CCl4 and T1-acetate, which were manifested by increased peroxidation of lipids and increased depletion of reduced glutathion in liver homogenates.

Interaction of chelating agents with cadmium in mice and rats.

The influence of several chelating agents (CaDTPA, ZnDTPA, CaEDTA, ZnEDTA, DMSA, D-penicillamine and DMPS, DMP and DDC) on the acute toxicity of CdCl2 and on the whole body retention and tissue distribution of cadmium after the IV application of 115mCdCl2 was compared in mice. The chelating agents were applied immediately after the application of cadmium. CaDTPA, ZnDTPA and DMSA appeared to be the most effective antidotes. However, DMSA increased the amount of cadmium retained in kidneys. The treatment of cadmium-poisoned mice with the combination of DMSA (IP) and ZnDTPA (SC) (all the compounds were injected in equimolar dose) decreased the toxicity of cadmium more than treatment with one chelating agents (given in a 2:1 dose). However, by studying the effect of these chelating agents and their combination of the retention and distribution of Cd in mice, it was demonstrated that the combined application of the antidotes showed little or no improvement over the results obtained with the most effective of the individual components. In the urine of rats injected with CdCl2 and treated with the chelating agents (CaDTPA, ZnDTPA, DMSA), the presence of cadmium complexes was demonstrated. The formation of mixed ligand chelates in vivo was not proved. Experiments in mice given a single injection of 115mCd-labeled Cd complexes of DMPS, DMSA and DTPA showed a high retention of cadmium in the organisms after the IV application of CdDMPS and CdDMSA complexes.