Protective effects of zinc on cadmium toxicity in rodents

A study of acute and subacute toxicity of cadmium ions [Cd(II)] was carried out on male Swiss mice and Sprague-Dawley rats with and without previous administration of zinc chloride. The LD₅₀ of Cd(II) as cadmium sulfate (ip) was lower in animals previously given 10 mg/kg of zinc(II) chloride (sc). Factors such as animal weight variations, biochemical parameters, and accumulation patterns of Cd(II) and Zn(II) were taken into consideration when the subacute toxicity was evaluated. Alteration of the activities of glutamic pyruvic transaminase (GPT) and of glutamic oxaloacetic transaminase (GOT) was observed in short-term-exposure (<6 h) cases. These alterations reverted to normal after 1 wk. The activity of alkaline phosphatase (ALP) and the concentrations of cholesterol and triglycerides in serum are also changed, especially so in the groups given CdSO₄ alone. In the experimental groups treated with ZnCl₂ prior to administration of cadmium, proteinuria was detected 5 wk after the treatment. Also at 5 wk, both Zn-treated and nontreated groups showed an abnormally low liver mass with respect to total body mass. Both Cd and Zn are retained preferentially in the liver but show also in the kidneys. If CdSO₄ and ZnCl₂ are given simultaneously, especially after 1 wk of treatment, Cd is accumulated in greater amounts in these organs when compared to the groups given only cadmium sulfate.     

Metal constitution of metallothionein influences inhibition of delta-aminolaevulinic acid dehydratase (porphobilinogen synthase) by lead.

This study was undertaken to evaluate the effect of Zn and Cd pretreatment on the inhibition of delta-aminolaevulinic acid dehydratase (ALAD; porphobilinogen synthase, EC 4.2.1.24) by Pb. Male CD rats were pretreated with 200 mumol of Zn/kg s.c. (subcutaneously) or 18 mumol of Cd/kg s.c., 48 and 24 h before assay of ALAD. Pretreatment with Zn resulted in activation of hepatic and renal ALAD and attenuated the inhibition of this enzyme by Pb in vitro. Pretreatment with Cd increased hepatic ALAD activity, and the inhibitory effect of Pb on the hepatic enzyme was attenuated in this group. In contrast with the situation in liver, pretreatment with Cd did not affect the activity of renal ALAD and did not alter the inhibitory effect of Pb on the renal enzyme. The Pb IC50 (concentration causing half-maximal inhibition) values for hepatic and renal ALAD in Zn-pretreated rats and for hepatic ALAD in Cd-pretreated rats were increased above control, whereas the IC50 for renal ALAD in Cd-pretreated rats was unchanged. Cytosolic binding patterns for the three metals were assessed by gel-filtration chromatography and disclosed that 203Pb was co-eluted with Zn and Cd bound to liver and kidney Zn-thioneins and liver Cd,Zn-thionein, although minimal binding of 203Pb to kidney Cd,Zn-thionein was observed. Estimation of the molar ratio of metals bound revealed Cd/Zn ratios of 2 and 5 for Cd,Zn-thioneins from liver and kidney respectively. The inhibition of purified ALAD by Pb was also attenuated by addition of purified Zn-thioneins and Cd,Zn-thioneins from liver and kidney in the following order: liver Zn-thionein = kidney Zn-thionein greater than liver Cd,Zn-thionein much greater than kidney Cd,Zn-thionein. Thus liver and kidney Zn-thioneins and liver Cd,Zn-thionein with a low Cd/Zn ratio readily decrease the free pool of Pb available to interact with ALAD. These data also demonstrate that the capacity of metallothionein to alter the intracellular distribution of Pb and mediate the inhibition of ALAD by Pb is dependent on the tissue source and relative metal constitution of the metallothionein.     

Separation and quantification of serum alkaline phosphatase isozymes in the rat by affinity electrophoresis

The purpose of this study was to examine the possibility of separation and quantification of serum alkaline phosphatase (ALP) isozymes in rats by wheatgerm lectin affinity electrophoresis. Cellulose acetate electrophoresis of the liver and bone ALPs without lectin results in overlapping bands, but in the presence of lectin, the mobility of the band of bone enzyme was retarded and well separated from the liver enzyme band. With this affinity electrophoretic method, we determined the serum ALP isozymes in fed and fasting rats grouped by age. As a result, the absolute activity of bone isozyme showed a downward trend with age in the fed and fasting rats. The serum ALP activity was steadily higher in fed rats than in fasting rats, and the increase was due to intestinal ALP isozyme. There was low activity bordering complete absence in liver isozyme under both nutritional conditions. The affinity electrophoretic method provided a rapid, reproducible, and relatively simple technique for further clinical characterization of ALP isozyme in the rat serum.     

Effect of cadmium,mercury and copper on partially purified hepatic flavokinase of rat

The effect of cadmium (Cd2+), mercury (Hg2+) and copper (Cu2+) was studied with partially purified flavokinase (ATP:riboflavin 5-phosphotransferase EC 2.7.1.26) from rat liver. All the divalent heavy metal cations inhibited flavokinase activity in a concentration-dependent manner. The inhibitory effect of cadmium on the enzyme was completely reversed by increasing concentration, of Zinc (Zn2+) indicating a competition between Zn2+ and Cd2+ for binding with the enzyme. A competition between riboflavin and Cd2+ is also evident from the present investigation. These observations hint at the possibility that Zn2+ and Cd2+ probably compete for the same site on the enzyme where riboflavin binds. However, inhibition of flavokinase by Hg2+ could not be reversed by Zn2+. Our studies further reveal that hepatic flavokinase appears to contain an essential, accessible and functional thiol group(s) which is evident from a concentration dependent inhibition of activity by sulfhydryl reagent s like parachloromercuribenzoate (PCMB), 5,5-dithiobis (2-nitrobenzoic acid)(DTNB), and N-ethylmaleimide (NEM). Inhibition of flavokinase by sulfhydryl reagents were protected, except in case of NEM inhibition, when the enzyme was incubated with thiol protectors like glutathione (GSH) and dithiothreitol (DTT). Furthermore, the enzyme could also be protected from the inhibitory effect of Cd2+ and Hg2+ by GSH and DTT suggesting that Cd2+ probably interacts with a reactive thiol group at or near the active site of enzyme in bringing about its inhibitory effect. (Mol Cell Biochem 167: 73-80, 1997)     

Effect of zinc supplementation on glutathione peroxidase activity and selenium concentration in the serum, liver and kidney of rats chronically exposed to cadmium

It was investigated whether the ability of zinc (Zn) to prevent cadmium (Cd)-induced lipid peroxidation may be connected with its impact on glutathione peroxidase (GPx) activity and selenium (Se) concentration. GPx and Se were determined in the serum, liver and kidney of the rats that received Cd (5 or 50 mg/L) or/and Zn (30 mg/L) in drinking water for 6 months in whose the protective Zn impact was noted (Rogalska J, Brzóska MM, Roszczenko A, Moniuszko-Jakoniuk J. Enhanced zinc consumption prevents cadmium-induced alterations in lipid metabolism in male rats. Chem Biol Interact 2009;177:142-52). Moreover, dependences between these parameters, and indices of lipid peroxidation (F(2)-isoprostane, lipid peroxides, oxidized low density lipoprotein cholesterol) as well as concentrations of Cd and Zn were estimated. The supplementation with Zn during the exposure to 5 mg Cd/L entirely antagonized the Cd-induced increase in GPx activity and Se concentration in the liver and kidney, but not in the serum. Zn administration during the treatment with 50 mg Cd/L totally or partially prevented from the Cd-caused decrease in GPx activity and Se concentration in the serum, liver and kidney. At the higher level of Cd exposure, GPx activity in the serum and tissues positively correlated with Se concentration. Moreover, numerous correlations were noted between GPx and/or Se and the indices of lipid peroxidation. The results indicate that the protective impact of Zn against the Cd-induced lipid peroxidation during the relatively high exposure might be connected with its beneficial influence on Se concentration and GPx activity in the serum and tissues, whereas this bioelement influence at the moderate exposure seems to be independent of GPx and Se.     

Aspects of the biochemical toxicology of cadmium.

Cadmium, in addition to producing a variety of toxic manifestations, is known to accumulate in certain "target" organs which include liver and kidney where histological and functional damage becomes apparent. The daily intraperitoneal injection of cadmium chloride for 21 or 45 days stimulated the activities of hepatic pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1, 6-diphosphatase and glucose-6-phosphatase elevated blood glucose and urea, and lowered hepatic glycogen in rats. Whereas chronic Cd treatment failed to alter adenosine-3', 5'-monophosphate phosphodiesterase (PDE) activity, cyclic AMP (cAMY and the activity of basal and fluoride-stimulated forms of hepatic adenylate cyclase (AC) were markedly increased. However, the cAMP binding to hepatic protein kinase was decreased as was the kinase activity ration. An acute dose of Cd decreased hepatic glycogen content and increased blood glucose, serum urea, and hepatic cAMP. Chronic exposure to Cd induced adrenal hypertrophy and augmented adrenal norepinephrine and epinephrine as well as the activity of adrenal tyrosine hydroxylase. This treatment decreased prostatic and testicular weights of mature rats. Although cAMP as well as AC activity of the prostate gland were reduced, cAMP binding to the prostatic protein kinase was increased as was the activity of the cAMP-dependent form of the enzyme. Testicular AC and PDE activities, however, were stimulated, although cAMP remained unaffected. Whereas the activities of the cAMP-dependent and the independent forms of testicular protein kinase were significantly depressed, the binding of cAMP to protein kinase from testes of Cd-treated rats was not affected. In most cases, the observed metabolic alterations persisted up to 28 days on cessation of Cd administration. Subacute Cd treatment suppressed pancreatic function as evidenced by lowered serum immunoreactive insulin (IRI) in presence of hyperglycemia, as well as by partial inhibition of phentolamine-stimulated increases in serum IRI. Although chronic Cd treatment failed to alter the concentration of brain stem norepinephrine and cerebrocortical acetylcholine esterase activity, serotonin levels of brain stem were depressed and the concentration of striatal dopamine and cerebrocortical acetylcholine were significantly elevated when compared with the values seen in control nonexposed animals.     

Bradykinin potentiating factor isolated from Buthus occitanus venom has a protective effect against cadmium-induced rat liver and kidney damage

Bradykinin and its related peptides are widely distributed in venomous animals, including scorpion. A peptide fraction isolated from the venom of the Egyptian scorpion Buthus occitanus was proved to have a bradykinin-potentiating activity. The aim of the present study was conducted to investigate whether the treatment with bradykinin potentiating factor (BPF) offers more beneficial effects in reversing cadmium-induced oxidative stress in rat liver and kidney. Adult male rats, equally divided into control and two treated groups, 10 animals in each group. group (I) was orally given (1 ml) saline and served as a control group; group (II) of rats was given cadmium chloride (4 mg/kg) alone, once daily an oral dose for 7 successive days; group (III) of rats was given ip injection (1 ml) BPF, once daily a dose for 7 successive days prior to CdCl₂ treatment and on the next 7 successive days with the same dose of cadmium as group II. Both organs were subjected to histopathological analysis with the light microscope. The activities of alanine aminotransferase (ALT), asparate aminotransferase (AST) and alkaline phosphatase (ALP) in serum were measured as indicators of the liver function. As parameters of the kidney function, creatinine, uric acid and urea concentrations in serum were determined. Also, malondialdehyde (MDA), reduced glutathione (GSH), super oxide dismutase (SOD) and catalase (CAT) were determined in both tissues. Cd exposure caused a significant decrease or inhibition in the activities of GSH, SOD, and CAT, with significant increase in the level of MDA, in versus to control groups in both liver and kidney. Also, when Cd was treated in co-administration with BPF induced increase or stimulation in the activity of GSH, SOD, and CAT, with significant decrease in the level of MDA when compared to Cd group in both organs. Histopathological changes of liver and kidney were also in accordance with the biochemical findings. Our data showed that Cd treatment induced histopathological alteration in the liver, severe hydropic degeneration in centrolobular zones. Inflammatory cells infiltration around the congested central vein and an obvious injury in some renal tubules. Bradykinin potentiating factor (BPF) administration prevented the histopathological alterations which observed in Cd-groups and both liver and kidney had essentially normal appearance in histopathological examination. In conclusion, BPF markedly ameliorated cadmium-induced liver and kidney tissue damage as evidenced by histological and biochemical examinations and acts as a potent scavenger of free radicals to protect the liver and kidney against the deleterious effect of acute cadmium intoxication.     

Reversal of Cadmium-Induced Thyroid Dysfunction by Selenium, Zinc, or Their Combination in Rat

The aim of this study was to evaluate the potential benefit of combined treatment with zinc (Zn) and selenium (Se) in reversing cadmium (Cd)-induced thyroid dysfunction compared to Se or Zn treatment alone in rats exposed to Cd. For this purpose, 30 adult male Wistar albino rats were equally divided into control and four treated groups receiving either 200 ppm Cd (as CdCl2), 200 ppm Cd + 500 ppm Zn (as ZnCl2), 200 ppm Cd + 0.1 ppm Se (as Na2SeO3), or 200 ppm Cd + 500 ppm Zn + 0.1 ppm Se in their drinking water for 35 days. The results showed that Cd exposure increased significantly the relative thyroid weight (RTW), the thyroid Cd concentration, and the serum thyroid stimulating hormone (TSH) level, whereas the serum thyroxine (T4) level was decreased compared to control rats. The treatment of Cd-exposed rats with Se alone only partially protected from the Cd-induced decrease in serum T4 level. The treatment of Cd-exposed animals with Zn alone partially protected against Cd-induced thyroid dysfunction by maintaining normal RTW and by decreasing Cd concentration in the thyroid. It also partially prevents Cd-induced decrease in serum T4 level. The combined treatment of Cd-exposed animals with Se and Zn induced a more significant decrease in the thyroid Cd concentration than the Zn supplement and a total correction of the RTW. This treatment was also more effective than that with Se or Zn alone in reversing Cd-induced decrease in serum T4 level and Cd-induced increase in serum TSH level. Se and Zn can have a synergistic role against Cd-induced thyroid dysfunction.     

A possible mechanism of induction and translocation into blood stream of rat alkaline phosphatase activity by bile duct ligation

We investigated the effects of bile duct ligation on alkaline phosphatase (ALP) activities in liver, calvarium, duodenum, and ileum in rats and its possible mechanism of action. ALP isozyme activities in the ligated rats were significantly elevated in the liver and duodenum, while those in the ileum and calvarium were markedly decreased. The ALP isozyme activity elevated by the ligation was obviously suppressed by prior administration of indomethacin, an inhibitor of prostaglandin synthesis. Moreover, phorbol ester also elevated the ALP activity as well as the phosphatase level in the ligated rat. However, other drugs, such as an inhibitor of protein kinase C and calmodulin, showed different effects: calmodulin stimulated an 11.0-, 1.3-, or 1.5-fold increase in ALP activity in the ileum, duodenum, or calvarium, respectively; whereas the hepatic enzyme activity was not affected. The induction by calmodulin was markedly different from that by the ligation. Moreover, imipramine, an inhibitor of protein kinase C, had little effect. These results suggest that prostaglandin is a possible ALP inducer in ligated rats, probably working by elevating the cAMP level. On the other hand, the ligation induced simultaneously de novo synthesis of the membranous and soluble ALP isozymes; and the release rate of the soluble enzyme was greater than that of the membranous isozymes, indicating that the soluble enzyme might be a main source of the induced serum ALP. Lectin affinity chromatography indicated that the soluble enzyme or induced serum enzyme may contain more fucose than that of the membranous one, suggesting that the sugar moiety in the ALP molecule may relate to the clearance of ALP from or its release into the circulation.     

Alkaline phosphatase in cholestatic and cirrhotic rats. A biochemical and histochemical study

Alkaline phosphatase (ALP) was studied by enzyme histochemical methods and by biochemical quantitations in rat livers with chronic bile duct obstruction and experimental cirrhosis. The most evident ALP increase was histochemically found in portal tracts of rats with bile duct obstruction and localized to the walls of proliferating blood vessels. Furthermore, a slight canalicular membrane enzyme increase was histochemically found in both groups, most evident in cirrhosis, whereas the biochemical assay of ALP in serum and liver from both pathological groups showed 3 times higher values compared to controls. The portal tracts did not seem to contribute to the serum increase, since the rise of serum ALP was similar in chronic bile duct obstruction and in experimental cirrhosis without changes of the portal tracts. It is concluded that the increase ALP activity in serum from rats with bile duct obstruction and cirrhosis mainly has a hepatocytic origin.     

Differential response of cadmium toxicity towards Mg2(+)-ATPase activity in hepatic and renal nuclear membrane in rats

Treatment with cadmium chloride (40mg/kg body wt/day) for three days led to a marked inhibition of Mg2(+)-ATPase activity in rat liver nuclear membrane, whereas it stimulated the enzyme in renal nuclear membrane. On 30 days treatment (15 mg/kg body wt/day) the effect was totally different i.e. stimulation of enzyme activity in the liver and inhibition in the kidney tissue. Arrhenius plot analysis of the enzyme activity showed significant increase in phase transition temperature only in liver tissue of rats subjected to acute treatment. Lineweaver Burk plots also showed differential effect of cadmium toxicity on the enzyme activity, i.e. while both Km and Vmax were changed in the liver, there was change only in Km of enzyme from kidney.     

Effect of simultaneous exposure to lead and cadmium on gonadotropin binding and steroidogenesis on granulosa cells: an in vitro study

Effects of lead (Pb) and cadmium (Cd) both alone or in combination on the binding of LH and FSH on isolated granulosa cells were studied. Granulosa cells isolated from proestrous rats were incubated (in vitro) with lead acetate and/or cadmium acetate (0.03 microM of Pb or Cd) for 1 hr. LH binding was dropped to 84% in Pb treated cells, 72.5% in Cd treated cells and 74.8% in combined metal treated cells compared to control. FSH binding dropped to 85.5% in Pb treated cells, 71.16% in Cd treated cells and 72.5% in combined metal treated cells compared to control. Activity of 17beta Hydroxy Steroid Dehydrogenase (17betaHSDH), a key steroidogenic enzyme was reduced by 52% in Cd and 37% in combined metal exposed cells whereas Pb exposed cells showed 31% reduction in the enzyme activity. Pretreatment with SH groups protectants (glutathione [GSH], dithiothretol [DTT]) and zinc caused an ameriolation in enzyme activity whereas Zn pretreatment showed an increase in gonadotropin binding in metal exposed cells. These results suggest that both Pb and Cd can cause a reduction in LH and FSH binding, which significantly alters steroid production in vitro and exerts a direct influence on granulosa cell function.     

Cadmium sensitivity differences between liver microsomal drug metabolizing enzyme systems of guinea-pig and rat

1. Male guinea-pigs (400-500 g) and rats (225-275 g) were given a single dose of cadmium chloride (CdCl2) (2 mg Cd2+/kg i.p.) and 72 hr later the liver microsomal drug metabolizing enzyme activities and Cd levels of tissues and microsomes were determined. 2. No significant differences were noted between Cd treated and control animal tissue weights of microsomal protein contents in either guinea-pigs or rats. 3. Cd treatment exhibited significant inhibition of the activities of aniline 4-hydroxylase and ethylmorphine N-demethylase and on the levels of cytochrome P-450 and cytochrome b5 of liver of both species but the degree of inhibition were not the same in the species; they were 23, 34, 16 and 10% in guinea-pigs and 58, 57, 25 and 13% in rats, respectively. 4. No activity changes were observed in liver NADPH-cytochrome c reductase of the species by Cd treatment. 5. The duration of hexobarbital sleeping time was significantly prolonged in both species. However, the prolongation was 1.6 fold in guinea-pigs but 3.4 fold in rats. 6. No significant differences were found between either tissue or microsomal Cd levels of guinea-pigs and rats.     

Antioxidant enzyme activity and lipid peroxidation in liver of female rats co-exposed to lead and cadmium: Effects of vitamin E and Mn2+

The oxidative status of liver of female rats exposed to lead acetate and cadmium acetate either alone or in combination at a dose of 0.05?mg/kg body wt intraperitoneally for 15 days was studied. After the administration of lead alone, the activity of superoxide dismutase (SOD) decreased in liver, whereas no changes were observed in catalase (CAT) activity, and glutathione (GSH) and thiobarbituric acid (TBARS) levels. Cadmium exposure and combined exposure to lead and cadmium led to decrease in GSH content and increased TBARS levels. Moreover, animals exposed to either cadmium alone or in combination with lead showed a decrease in SOD activity and an increase in CAT activity. The in vitro experiments showed that vitamin E failed to restore the antioxidant enzyme activities in metal treated postmitochondrial supernatant fraction of liver. But Mn²⁺ ions protected the mitochondria from lipid peroxidation and could completely restore Mn-superoxide dismutase (Mn-SOD) activity following metal intoxication. The results of this study indicate that despite the ability of lead and cadmium to induce oxidative stress the effect in liver is not intensified by combined exposure to both lead and cadmium. The observed changes in various oxidative stress parameters in the liver of rats co-exposed to lead and cadmium may result from an independent effect of lead and /cadmium and also from their interaction such as changes in metal accumulation and content of essential elements like Cu, Zn and Fe. These results suggest that when lead and cadmium are present together in similar concentrations, cadmium mediates major effects due to its more reactive nature.     

Variation in the distribution of trace elements in hepatoma

There are many reports of reduction of zinc level and rise of copper level in serum of patients with liver disease. However, there are a few reports that compare the trace elements in tumor tissues and nontumor tissues of the liver with hepatoma. We studied trace element distribution in tumor tissues and nontumor tissues of liver with hepatoma and compared them with data from normal liver tissues. Zinc (Zn), copper (Cu), selenium (Se), cadmium (Cd), mercury (Hg), and iron (Fe) were chosen as the trace elements to be observed. We observed falls of Zn, Cd, and Hg levels in tumor tissues and the rise of Cu level as a result of this investigation. Zn, Cd, and Hg levels in tumor tissues were significantly lower than those in nontumor tissues and Zn, Cd, and Hg levels in nontumor tissues were significantly lower than in normal liver tissues. This tendency was clearer for Cd and Hg than for Zn. Although the distribution of Cu was not significant, a distribution contrary to that of Zn was shown. These findings indicate that the distribution of Zn, Cd, and Hg can serve as supportive evidence that could be useful as a tumor marker. Selenium showed almost the same accumulation tendency among tumor tissues, nontumor tissues, and normal livers. Although correlation was observed among most metals in the normal liver, there was almost no correlation in tumor tissues.     

Protection against cadmium toxicity and enzyme inhibition by dithiothreitol

In the present in vivo studies the alterations in cation transporting enzymes of the brain, kidney and liver tissues were assessed at intervals between 0 to 48 h after a single, acute (10 mg kg-1, i.p.) dose of cadmium (Cd). The inhibition of Na+-K+-ATPase during the first 24 h does not parallel the changes in K+-PNPPase suggesting differential effects on phosphorylation and dephosphorylation steps of the overall ATPase reaction. Between 30 min to 2 h the inhibition in enzyme activity was steep (27 per cent in brain, 54 per cent in liver) followed by a rapid reversal between 2-6 h. This critical period may correspond to the time of induction of metallothionein. This enzyme reversal was followed by a significant decrease in Na+-K+ ATPase (40-68 per cent) and K+-PNPPase (44-60 per cent) between 24 to 48 h. A similar pattern was observed in Ca2+-ATPase in all the three tissues. A 33 per cent mortality was observed in rats after 48 h of cadmium challenge. Administration of dithiothreitol (DTT, 20 mg kg-1, i.p.) to CdCl2 pretreated rats at 24 h resulted in mortality reduced from 33 per cent to 0 and reversal in the inhibition of Na+-K+-ATPase in brain and kidney and Ca2+-ATPase in brain. Since protection of brain and kidney enzymes by DTT paralleled its protection against Cd toxicity, their inhibition by Cd may, in part, constitute the biochemical basis of Cd toxicity.     

Effects of exogenous metallothionein on acute cadmium toxicity in rats

The present study was carried out to evaluate the effect of exogenously administered metallothionein (MT) to rats exposed to high cadmium levels. A total of 72 rats were used in the study. The animals were divided into three groups: controls, Cd administered, and Cd+MT. Cadmium was administered by subcutaneous injection of cadmium(II) chloride at a dose of 3.5 mg/kg for 7 d. In addition to CdCl₂, 30 μmol/kg MT was administered to the second group of rats (group II). Control rats received 0.5 mL physiologic serum via subcutaneous injection. Eight rats from each group were sacrificed on the 1st, 3rd, 5th, and 7th day after administration of the compounds. Liver, kidney, and blood samples were harvested. Levels of malondialdehyde (MDA), glutathione peroxidase (GSH-Px), serum ALT, AST, BUN, ALP, creatinine, and urea were measured. MDA levels in group I were observed to increase starting from d 1 compared to group II (p<0.05). Although MDA levels in group II were higher than controls (p<0.05), they were lower, especially in liver and blood, compared to group II. Erythrocyte GSH-Px activity levels were determined to decrease starting from d 1 in both groups (p<0.05). Decreases in GSH-Px activity levels in group II were less than group I. Serum creatinine levels in both groups were increased significantly compared to controls (p<0.05); the increase in group I was higher than group II. Serum ALT, AST, and ALP levels in group I increased to very high levels compared to controls, whereas increases in group II were at moderate levels (p<0.05). Although serum BUN levels were determined to be reduced, there was no significant change among the groups. Serum urea levels in both groups were higher than controls. Based on our results, it is possible to postulate that exogenous MT can act as antioxidant against Cd toxicity and lipid peroxidation.     

Protective effect of zinc against cadmium hepatotoxicity depends on this bioelement intake and level of cadmium exposure: a study in a rat model

It was estimated, in a rat model of moderate and relatively high chronic human exposure to cadmium (Cd), whether enhanced zinc (Zn) consumption may prevent Cd-induced liver injury and if the possible protective effect of this bioelement depends on its intake. For this purpose, the structure and function of the liver of the rats that received Zn (30 and 60 mg/l) or/and Cd (5 and 50 mg/l) for 6 months were evaluated. The treatment with Cd led to, dependent on the exposure level, pathological changes in the liver, including enhanced apoptosis and induction of inflammatory and necrotic processes. Moreover, the serum activities of hepatic marker enzymes (alanine transaminase and aspartate transaminase) and the concentration of proinflammatory cytokine – tumor necrosis factor α were increased. The supplementation with 30 and 60 mg Zn/l (enhancing daily Zn intake by 79% and 151%, respectively) partially or totally prevented from some of the Cd-induced changes in the liver structure and function; however, it provided no protection from necrosis, and the administration of 60 mg Zn/l during the higher Cd exposure even intensified this process. At both levels of Cd treatment, the use of 30 mg Zn/l was more effective in preventing liver injury than that of 60 mg Zn/l. The hepatoprotective impact of Zn may be explained, at least partly, by its antioxidative, antiapoptotic and anti-inflammatory action, ability to stimulate regenerative processes in the liver tissue, and indirect action resulting in a decrease in the liver pool of the non-metallothionein-bound Cd²⁺ ions able to exert toxic action. The results provide strong evidence that enhanced Zn consumption may be beneficial in protection from Cd hepatotoxicity; however, its excessive intake at relatively high exposure to Cd may intensify liver injury.     

Antioxidant enzyme activity and lipid peroxidation in liver of female rats co-exposed to lead and cadmium: effects of vitamin E and Mn2+

The oxidative status of liver of female rats exposed to lead acetate and cadmium acetate either alone or in combination at a dose of 0.05 mg/kg body wt intraperitoneally for 15 days was studied. After the administration of lead alone, the activity of superoxide dismutase (SOD) decreased in liver, whereas no changes were observed in catalase (CAT) activity, and glutathione (GSH) and thiobarbituric acid (TBARS) levels. Cadmium exposure and combined exposure to lead and cadmium led to decrease in GSH content and increased TBARS levels. Moreover, animals exposed to either cadmium alone or in combination with lead showed a decrease in SOD activity and an increase in CAT activity. The in vitro experiments showed that vitamin E failed to restore the antioxidant enzyme activities in metal treated postmitochondrial supernatant fraction of liver. But Mn²⁺ ions protected the mitochondria from lipid peroxidation and could completely restore Mn-superoxide dismutase (Mn-SOD) activity following metal intoxication. The results of this study indicate that despite the ability of lead and cadmium to induce oxidative stress the effect in liver is not intensified by combined exposure to both lead and cadmium. The observed changes in various oxidative stress parameters in the liver of rats co-exposed to lead and cadmium may result from an independent effect of lead and /cadmium and also from their interaction such as changes in metal accumulation and content of essential elements like Cu, Zn and Fe. These results suggest that when lead and cadmium are present together in similar concentrations, cadmium mediates major effects due to its more reactive nature.     

Time dependent study to evaluate the efficacy of zinc on hepatic marker enzymes and elemental profile in serum and liver of protein deficient rats

This study was designed to determine the time dependent protective effects of zinc sulfate on the serum and liver marker enzymes along with elemental profile in protein deficient Sprauge Dawley (S.D.) female rats. Zinc sulfate in the dose of 227 mg/l in drinking water was administrated to normal control as well as protein deficient rats for a total duration of 8 weeks. The effects of different treatments were studied on enzymes like alkaline phosphatase (ALP), aspartate aminotransferases (AST) and alanine aminotransferases (ALT) in rat serum at different time intervals of 1, 2, 4 and 8 weeks and in the rat liver at the end of study. The status of different essential elements in liver was also studied. The serum ALP activity got significantly depressed when estimated at the intervals of 4 and 8 weeks. Activity of serum ALT was significantly increased after 4 weeks interval in protein deficient rats and the increasing trend continued upto 8 weeks of protein deficiency. On the other hand, activity of AST showed a significant increase just after 2 weeks and activity continued to be increased up to 8 weeks. Moreover activities of all the hepato marker enzymes showed a significant increase in liver of protein deficient rats. Interestingly, supplementation of Zn to protein deficient rats helped in regulating the altered activities of ALP, AST and ALT both in serum and liver. However, zinc treatment alone to normal rats did not indicate any significant change in the activities of all the enzymes in liver as well serum except at the interval of 2 weeks where a marginal increase in the activity of AST was seen. It has also been observed that concentrations of zinc, copper, iron and selenium were found to be decreased significantly in protein deficient animals. However, the levels of these elements came back to within normal limits when zinc was administrated to protein deficient rats. Published online December 2004