Antiangiogenic effect of Lygodium flexuosum against N-nitrosodiethylamine-induced hepatotoxicity in rats

The antiangiogenic effect of Lygodium flexuosum extract was evaluated in Wistar rats intoxicated with N-nitrosodiethylamine (NDEA) in preventive and curative models. In preventive groups, NDEA was administered for 20 weeks. Daily doses of L. flexuosumn-hexane extract (200mg/kg) started 1 week before the onset of NDEA intoxication and continued for 20 weeks. In curative animals, NDEA was administered for 20 weeks followed by treatment with the n-hexane extract of L. flexuosum for 28 days. Rats intoxicated with NDEA had elevated levels of serum gamma-GT, AST, ALT, LDH levels and hepatic MDA and decreased levels of hepatic GSH. When treated with L. flexuosum extract had normal levels of gamma-GT, AST, ALT, LDH levels, hepatic MDA and GSH. NDEA administered rat liver showed an overexpressed levels of angiopoietins 1 (Ang-1) and 2 (Ang-2) and its receptor Tie-2 mRNA. L. flexuosum extract treatment significantly (p相似文献   

Antioxidant and anticarcinogenic activity of Lycovin--an indigenous herbal preparation

Aqueous extract of Lycovin has been found to be a potent inhibitor of lipid peroxide formation, (IC50 = 500 micrograms/ml) and scavenger of hydroxyl radical (IC50 = 44 micrograms/ml) and superoxide radical (IC50 = 30 micrograms/ml) in vitro. Lycovin syrup 1.5 ml and 7.5 ml/kg body wt administered orally, reduced the development of sarcoma induced by 20 MC by 35% and 70% respectively. Lycovin syrup was also found to inhibit the hepatocarcinogenesis induced by NDEA. The tumour incidence was 100% in the control group, while none of the drug treated animals developed tumour. Liver weight, gamma-glutamyl transpeptidase (GGT), GSH-S-transferase (GST), reduced glutathione, (GSH) and aniline-4-hydroxylase in liver were elevated in NDEA alone treated animals. The serum parameters indicative of liver injury such as bilirubin, lipid peroxides, alkaline phosphatase and glutamate pyruvate transaminase were also elevated by NDEA administration. These elevated parameters were significantly reduced in animals treated with Lycovin syrup along with NDEA in a dose dependent manner. Even though the exact mechanism of action is not known at present, the observed anticarcinogenic activity may be due to the inhibition of P.450 enzyme activity and subsequent inhibition of the production of the ultimate carcinogen as well as scavenging of oxygen free radicals during promotion of the transformed cell.     

Suppression of N-nitrosodiethylamine induced hepatocarcinogenesis by silymarin in rats

Antioxidants are one of the key players in tumorigenesis, several natural and synthetic antioxidants were shown to have anticancer effects. In the present investigation the efficacy of silymarin on the antioxidant status of N-nitrosodiethylamine (NDEA) induced hepatocarcinogenesis in Wistar albino male rats were assessed. The animals were divided into five groups. The animals in the groups 1 and 3 were normal control and silymarin control, respectively. Groups 2, 4 and 5 were administered with 0.01% NDEA in drinking water for 15 weeks to induce hepatocellular carcinoma (HCC). Starting 1 week prior to NDEA administration group 4 animals were treated with silymarin in diet for 16 weeks, 10 weeks after NDEA administration group 5 animals were treated with silymarin and continued till the end of the experiment period (16 weeks). After the experimental period the body weight, relative liver weight, number of nodules, size of nodules, the levels of lipid peroxidation, glutathione (GSH), and the activities of antioxidant enzymes were assessed in both haemolysate and liver tissue. In group 2 hepatocellular carcinoma induced animals there was an increase in the number of nodules, relative liver weight. The levels of lipid peroxides were elevated with subsequent decrease in the body weight, (glutathione) GSH, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), glucose-6-phosphate dehydrogenase (G6PD). In contrast, silymarin + NDEA treated groups 4 and 5 animals showed a significant decrease in the number of nodules with concomitant decrease in the lipid peroxidation status. The levels of GSH and the activities of antioxidant enzymes in both haemolysate and liver were improved when compared with hepatocellular carcinoma induced group 2 animals. The electron microscopy studies were also carried out which supports the chemopreventive action of the silymarin against NDEA administration during liver cancer progression. These findings suggest that silymarin suppresses NDEA induced hepatocarcinogenesis by modulating the antioxidant defense status of the animals.     

Adrenergic mechanisms of the regulation of stages of chemical carcinogenesis: role of presynaptic receptors

A modifying effect of a catecholamine precursor (L-DOPA, 20 mg/kg, intraperitoneally) on various stages (initiation and promotion) of hepatocarcinogenesis, induced by N-nitrosodiethylamine (NDEA, 85 mg per 1 litre of tap water) was studied in chronic experiments on 150 male rats. L-DOPA administration prior to NDEA (influence on initiation) stimulated hepatocarcinogenesis considerably, while its administration after NDEA (influence on promotion) inhibited the realization of a carcinogenic effect. A statistically significant decrease in noradrenaline hypothalamus content was identified during early stages of chemically induced neoplastic transformation of hepatic cellular elements (stages of diffuse and focal proliferation). The results are discussed in terms of the regulatory role of the tone of the adrenergic autonomous nervous system component at the level of presynaptic inhibitory receptors in realization of the chemical carcinogenic effect.     

Protective Effects of Garlic and Silymarin on NDEA-Induced Rats Hepatotoxicity

Background ­— The present study was conducted to investigate the chemopreventive effects of garlic extract and silymarin on N-nitrosodiethylamine (NDEA) and carbon tetrachloride (CCl₄)-induced hepatotoxicity in male albino rats. Methods and Results — Animals were pretreated with garlic, silymarin or both for one week prior to the injection of NDEA. Then animals received a single injection of NDEA followed by weekly subcutaneous injections of CCl₄ for 6 weeks. Oral administration was then continued along with the injection of CCl₄ for the duration of the experiment. Serum aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), hepatic lipid peroxidation (LPO), superoxide dismutase (SOD), reduced glutathione (GSH), glutathione-S-transferase (GST) and glutathione reductase (GSR) were measured. Injection of NDEA induced a significant elevation in serum AST, ALT and ALP. In the liver, NDEA increased oxidative stress through the increase in LPO and decrease in SOD, and GSH-dependent enzymes. Although administration of garlic or silymarin significantly reduced the liver toxicity, combined administration was more effective in preventing the development of hepatotoxicity. Conclusion — These novel findings suggest that silymarin and garlic have a synergistic effect, and could be used as hepatoprotective agents against hepatotoxicity.     

Protective effects of garlic oil on hepatocarcinoma induced by N-nitrosodiethylamine in rats

To investigate the protective effects and the possible mechanisms of garlic oil (GO) against N-nitrosodiethylamine (NDEA)-induced hepatocarcinoma in rats, Wistar rats were gavaged with GO (20 or 40 mg/kg) for 1 week, and then were gavaged with GO and NDEA (10 mg/kg) for the next 20 weeks. The changes of morphology, histology, the biochemical indices of serum, and DNA oxidative damage of liver were examined to assess the protective effects. Lipid peroxidation (LPO), antioxidant defense system, and apoptosis-related proteins were measured to investigate potential mechanisms. At the end of the study (21 weeks), GO administration significantly inhibited the increase of the nodule incidence and average nodule number per nodule-bearing liver induced by NDEA, improved hepatocellular architecture, and dramatically inhibited NDEA-induced elevation of serum biochemical indices (alanine aminotransferase , aspartate aminotransferase, alkaline phosphatase and gamma-glutamyl transpeptidase) and hepatic 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in a dose-dependent manner. The mechanistic studies demonstrated that GO counteracted NDEA-induced oxidative stress in rats illustrated by the restoration of glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), glutathione peroxidase (GPx), glutathione-S-transferase (GST) levels, and the reduction of the malondialdehyde (MDA) levels in liver. Furthermore, the mRNA and protein levels of Bcl-2, Bcl-xl, andβ-arrestin-2 were significantly decreased whereas those of Bax and caspase-3 were significantly increased. These data suggest that GO exhibited significant protection against NDEA-induced hepatocarcinogenesis, which might be related with the enhancement of the antioxidant activity and the induction of apoptosis.     

Hepatic and renal oxidative stress in acute toxicity of N-nitrosodiethylamine in rats

Nitrosoamines such as N-nitrosodiethylamine (NDEA) produce oxidative stress due to generation of reactive oxygen species and may alter antioxidant defence system in the tissues. NDEA was administered ip as a single dose to rats in LD50 or in lower amounts and the animals were sacrificed after 0-48 hr of treatment. The results showed that lipid peroxidation in liver increased, however no significant increase in kidney LPO was observed after NDEA administration. Superoxide dismutase (SOD) and glutathione reductase (GSH-R) activity increased in liver, however, catalase (CAT) activity in liver was inhibited in NDEA treated rats. Kidney showed an increase in SOD activity after an initial decrease along with increase in GSH-R activity in NDEA treated rats. However, kidney CAT activity was not significantly altered in NDEA intoxicated rats. Serum transaminases, serum alkaline phosphatase blood urea nitrogen, serum creatinine and scrum proteins were elevated in NDEA treated rats. The results indicate NDEA-induced oxidative stress and alteration in antioxidant enzymes in liver and kidney to neutralise oxidative stress.     

Protective role of Vitamin E pre-treatment on N-nitrosodiethylamine induced oxidative stress in rat liver

Nitrosamine compounds are known hepatic carcinogens. In the metabolism of nitrosamines, such as N-nitrosodiethylamine (NDEA), there is evidence of the formation of reactive oxygen species (ROS) resulting in oxidative stress, which may be one of the factors in the etiology of cancer. The formation of ROS may alter the antioxidant system, while the presence of Vitamin E may counteract NDEA induced oxidative stress. This study was planned to determine whether pre-treatment with Vitamin E (40 mg/kg body weight, i.p., twice a week for 4 weeks) to NDEA induced rats provides protection against oxidative stress in liver caused by the carcinogen. A single necrogenic dose of NDEA (200mg/kg body weight) was administered i.p. to the male albino rats with or without Vitamin E pre-treatment and the animals were sacrificed on Days 7, 14 or 21 after the administration of NDEA. The result showed enhanced levels of hepatic lipid peroxidation (LPO) and conjugated dienes of NDEA treated rats as the indices of oxidative stress, however, Vitamin E pre-treated rats administered NDEA showed decreased LPO and conjugated dienes (Day 21). Superoxide dismutase (SOD) activity in liver was not altered significantly in NDEA treated rats with or without Vitamin E pre-treatment. Catalase (CAT) activity was inhibited with NDEA treatment, however, Vitamin E pre-treatment showed recovery in hepatic CAT activity (Days 14 and 21). Total and Se-glutathione peroxidase (GSH-Px) activities and glutathione-S-transferase (GST) activity in liver increased in NDEA treated rats irrespective of Vitamin E pre-treatment. Glutathione reductase (GSH-R) activity as well as total glutathione (GSH) content in liver decreased in NDEA treated animals, both of which were recovered in Vitamin E pre-treated rats administered NDEA. Activities of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) were increased significantly following NDEA treatment to rats with or without Vitamin E pre-treatment. The activities of AST and ALT enzymes were significantly reduced on Days 14 and 21 and ALP activity was reduced on Day 21 in NDEA+Vitamin E treated animals when compared to NDEA treated alone. LDH enzyme activity was normalized on Day 14 in Vitamin E pre-treated animals administered NDEA. However, the AST, ALT and ALP enzyme activities remained high in all treatment groups as compared to control group. Normal control and Vitamin E treated alone rats revealed normal histology of liver. On the other hand, NDEA treated animals showed alterations in normal hepatic histoarchitecture, which comprised of necrosis and vacuolization of the cells. However, the rats treated with Vitamin E+NDEA showed that the liver cells were normal, with very little necrosis (Day 21). This study concludes that the pre-treatment with Vitamin E prior to the administration of NDEA, reduced the degree of oxidative stress, although this vitamin produced only slight changes in the hepatic injury, in a time-dependent manner.     

3-Methylcholanthrene induces phenobarbital-induced cytochrome P-450 hemoprotein in fetal liver and not cytochrome P-448 hemoprotein induced in maternal liver of rats

The characteristic nature of the drug-metabolizing system in fetal liver microsomes of rats was investigated. The aminopyrine(AM)- and the hexobarbital (HB)-metabolizing activities in fetal liver microsomes of the 21st day of pregnancy were induced by the maternal administration of 3-methylcholanthrene (3-MC) once daily on the 18th and the 19th day of pregnancy, while they were inhibited in maternal liver microsomes. The inductions of the AM- and the HB-metabolizing enzymes in fetal liver microsomes of rat by the maternal administration of 3-MC occurred exclusively in fetal period and simultaneously hemoprotein like phenobarbital-induced type P-450 different from that in maternal liver microsomes was newly induced in fetal liver microsomes of rats.     

The protective role of ellagitannins flavonoids pretreatment against N-nitrosodiethylamine induced-hepatocellular carcinoma

Ellagitannins are esters of glucose with hexahydroxydiphenic acid; when hydrolyzed, they yield ellagic acid (EA), the dilactone of hexahydroxydiphenic acid. EA has been receiving the most attention, because it has potent antioxidant activity, radical scavenging capacity, chemopreventive and antiapoptotic properties. Hepatocellular carcinoma (HCC) is the most frequent primary malignancy of liver, and accounts for as many as one million deaths worldwide in a year. The aim of the present study was to evaluate the antioxidant and chemopreventive efficiency of ellagic acid against N-nitrosodiethylamine (NDEA) induced hepatocarcinogenesis in rats. Rats were classified into four groups as follows: normal control group, group injected i.p. with a single dose (200 mg/kg b.wt.) of NDEA, third group daily administered orally EA with a dose of 50 mg/kg b.wt. for 7 days before and 14 days after NDEA administration, and fourth group received a similar dose of EA for 21 days after the dose of NDEA administration. The model of NDEA-injected hepatocellular carcinomic (HCC) rats elicited significant declines in liver antioxidant enzyme activities; glutathione peroxidase (GPX), gamma glutamyl transferase (γ-GT) and glutathione-S-transferase (GST), with a reduction in reduced glutathione (GSH) and serum total protein with concomitant significant elevations in tumor markers arginase and α-l-fucosidase, and liver enzymes; aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and glutathione-S-transferase (GST), glucose-6-phosphate dehydrogenase (G6PD), direct and total bilirubin. The oral administration of EA as a protective agent, produced significant increases in tested antioxidant enzyme activities and serum total protein concomitant with significant decreases in the levels of tumor markers arginase and α-l-fucosidase as well as liver enzymes, direct and total bilirubin. Similarly, the oral administration of EA, as a curative agent produced similar changes to those when EA was used as a protective agent, but to a lesser extent. In addition, it was noted that HCC rats exhibited a degree of DNA fragmentation; however, EA administration partially inhibited the DNA fragmentation. Therefore, EA has the ability to scavenge free radicals, prevent DNA fragmentation, reduce liver injury and protect against oxidative stress.     

The chemopreventive effect of Ginkgo biloba and Silybum marianum extracts on hepatocarcinogenesis in rats

Background/objective

This study was designed to evaluate the potential chemopreventive activities of Ginkgo biloba extract (EGb) and Silybum marianum extract (silymarin) against hepatocarcinogenesis induced by N-nitrosodiethylamine (NDEA) in rats.

Methods

Rats were divided into 6 groups. Group 1 served as normal control rats. Group 2 animals were intragastrically administrated NDEA at a dose of 10 mg/kg five times a week for 12 weeks to induce hepatocellular carcinoma (HCC). Groups 3 and 4 animals were pretreated with silymarin and EGb respectively. Groups 5 and 6 animals were posttreated with silymarin and EGb respectively. The investigated parameters in serum are alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyltransferase (GGT) and vascular endothelial growth factor (VEGF). The investigated parameters in liver tissue are malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR) and comet assay parameters.

Results

In NDEA group, MDA level was elevated with subsequent decrease in GSH level and SOD, GPx and GR activities. In addition, NDEA group revealed a significant increase in serum ALT, AST and GGT activities and VEGF level. Furthermore, NDEA administrated animals showed a marked increase in comet assay parameters. These biochemical alterations induced by NDEA were confirmed by the histopathological examination of rat livers intoxicated with NDEA that showed an obvious cellular damage and well differentiated HCC. In contrast, silymarin+NDEA treated groups (3&;5) and EGb+NDEA treated groups (4&;6) showed a significant decrease in MDA level and a significant increase in GSH content and SOD, GPx and GR activities compared to NDEA group. Silymarin and EGb also beneficially down-regulated the increase in serum ALT, AST, GGT activities and VEGF level induced by NDEA. In addition, silymarin and EGb significantly decreased comet assay parameters. Histopathological examination of rat livers treated with either silymarin or EGb exhibited an improvement in the liver architecture compared to NDEA group.

Conclusions

The obtained findings suggested that silymarin and EGb may have beneficial chemopreventive roles against hepatocarcinogenesis through their antioxidant, antiangiogenic and antigenotoxic activities.     

N-nitrosodiethylamine genotoxicity evaluation: a cytochrome P450 induction study in rat hepatocytes

In rats, N-nitrosodiethylamine (NDEA) induces tumors mainly in the liver. This could be because various enzymes are responsible for the metabolic activation of NDEA, besides the hepatic NDEA metabolizing enzyme, CYP2E1. We examined NDEA genotoxicity and cytotoxicity in primary cultures of female rat hepatocytes; we also looked at how it affected CYP mRNA expression. Single incubation with 0.9% NaCl resulted in a mean of 0.2% apoptotic cells, which doubled with 105 μg NDEA/mL. The frequency of necrosis with NDEA treatment was also doubled. Besides the cytotoxic effects, there was also a 4-fold decrease in mitotic index and a 3-fold decrease in the percentage of cells with micronuclei. A significant increase in micronucleus cells when hepatocytes were incubated with 2.1 μg NDEA/mL suggests that DNA repair was inactive. The chromosomal aberration evaluation revealed a discrete dose-response curve. Treatment with NDEA induced increases in CYP mRNA: CYP2B2 (1.8 times) and CYP2E1 (1.6 times) with non-cytotoxic NDEA concentrations (0.21-21 μg/mL). CYP2B1 mRNA levels decreased at 0.21 μg NDEA/mL (2.5-fold), while CYP4A3 mRNA decreased 1.3-fold. NDEA treatment at 2.1 μg/ mL induced a 1.9-fold increase in CYP3A1 mRNA. Understanding the cumulative effects in target cells during precarcinogenesis is crucial to understanding the mode of action of potential carcinogens and in order to develop comprehensive chemical toxicity profiles.     

Lycopene modulates initiation of N-nitrosodiethylamine induced hepatocarcinogenesis: Studies on chromosomal abnormalities,membrane fluidity and antioxidant defense system

Oxidative damage due to free radicals generated during nitrosamine metabolism has been suggested as one of the major cause for the initiation of hepatocarcinogenesis. Lycopene, is a well known antioxidant and have promising preventive potentials, however the mechanism of action remain hypothetical and unclear. To investigate the involvement of lycopene extracted from tomatoes (LycT) against oxidative stress induced deleterious effect of N-nitrosodiethylamine (NDEA) on cellular macromolecules, female Balb/c mice were divided in four groups: Control, NDEA (cumulative dose of 200 mg NDEA/kg body weight injected intraperitoneally in 8 weeks), LycT (5 mg/kg body weight given orally on alternate days, throughout the study) and LycT + NDEA (co-administration of LycT and NDEA). NDEA treatment commenced after 2 weeks of LycT administration. At the end of NDEA exposure i.e., at 10th week, enhanced activities of hepatic phase I enzymes, levels of reactive oxygen species (ROS), lipid peroxidation (LPO) was observed in NDEA group which may have contributed in chromosomal aberrations, enhanced micronucleated cell score, membrane fluidity and serum liver marker enzymes. A significant decrease in enzymatic and non-enzymatic antioxidant system could delineate the mechanism behind such NDEA insults. LycT pre-treatment to NDEA challenged group showed lower chromosomal abnormalities, micronucleated cells score, ROS, LPO levels and liver enzymes. Lycopene aids in normalizing the membrane fluidity and enhancing the activity of antioxidant enzymes and reduced glutathione which could account for the reduced oxidative damage in LycT + NDEA group. It seemed that lycopene supplementation target multiple dys-regulated pathways during initiation of carcinogenesis. Thus, dietary supplementation with lycopene can serve as an alternate measure to intervene the initiation of carcinogenesis.     

Chemopreventive effect of orange oil on the development of hepatic preneoplastic lesions induced by N-nitrosodiethylamine in rats: an ultrastructural study

Orange peel oil is used extensively as an approved flavour enhancer in fruit drinks, carbonated beverages and as a scenting agent in soaps and cosmetics. Limonene, which is a monocyclic monoterpene is present in orange peel oil from 90 to 95% (w/w). Monoterpenes have been shown to be very effective chemopreventive agents against several rodent tumors and are currently in clinical trials. However, not much information is available regarding the ultrastructural changes associated with the chemopreventive effects of the monoterpenes. The effect of orange oil on the suppression of preneoplastic hepatic lesions during N-nitrosodiethylamine (DEN) induced hepatocarcinogenesis was studied electron microscopically. Rats were administered 200 ppm DEN through drinking water for a period of 1 month. After an interval of 2 weeks, the animals were administered orange oil by gavage for a period of 5 1/2 months. The chemopreventive effect of orange oil was monitored on the basis of liver weight profile, histological pattern by light microscopy and ultrastructural alterations by electronmicroscopy. Orange oil administration following DEN treatment showed decreased liver weights, increased intercellular gap junctional complexes, cell density and polarity when compared with only the DEN treated rats. In the present study chemopreventive effect of orange oil on DEN-induced hepatic preneoplasia in rats which is associated with the restoration of the normal phenotype and upregulation of junctional complexes has been demonstrated.     

Modification of DNA-specific methylation in tissues of healthy and tumor bearing (sarcoma 45) rats under the effect of an active alkylating cancerolytic agent

The content of 5-methyl cytosine (5-MC) in the DNA preparations from organs and tissues of healthy and tumour-bearing (sarcoma 45) rats and the effect of an alkylating cancerolytic agent on DNA methylation in vivo were studied. The 5-MC content in the DNA preparations from liver, spleen and testicles of tumour-bearing rats and tumour cells was increased, the maximal increase being observed in liver and spleen DNAs (1,71 and 1,70 mol.%, respectively) and in sarcoma DNA (1,93 mol.%) on the 8th post-inoculation day. On the 8th and 15th day following daily injections of the cancerolytic agent the 5-MC content in the DNAs from liver and spleen of the control animals was decreased in a number of cases almost down to normal level (1,00 mol.%). Tumour DNA did not differ from normal tissue DNA with respect to Tmelt and GC content; however, its differential melting curve revealed an additional "shoulder" within the temperature range of 56--60 degrees, which was partly removed after addition of the cancerolytic agent. It was assumed that the changes in the methylation level and secondary structure of DNA can be due to the cancerolytic activity of the preparation.     

Hepatoprotective and antioxidant properties of Suaeda maritima (L.) dumort ethanolic extract on concanavalin-A induced hepatotoxicity in rats

Hepatoprotective and antioxidant properties of Suaeda maritima (L.) Dumort on concanavalin-A induced stress in Wistar albino rats have been reported. Rats were administered with ethanolic extract of Suaeda maritimna at the concentration of 75, 150 and 300 mg/kg of body wt. for 9 days and concanavalin-A was administrated (iv) 12 mg/kg on 9th day. Rats in concanavalin-A administered group showed elevated levels of AST, ALT, ALP and bilurubin. Pretreatment of rats with ethanolic extract (300 mg/kg) significantly reduced these serum parameters compared to concavalin-A administered group. Histopathological examination of liver sections showed that, normal liver architecture was disturbed by hepatotoxin intoxication. The extract treated group and silymarin treated group retained the normal cell architecture, although less visible changes were observed. Preliminary phytochemical analysis showed the presence of triterpenioids and may be responsible for the hepatoprotective activity. The LD50 was calculated as 3 g/kg of the body weight. IC50 values of hydroxyl (52.21+/-1.32 microg/ml) and nitric oxide radicals (09.14+/-0.94 microg/ml) scavenging results showed comparable activity with vitamin-C. Results of this study may be useful for the development of herbal medicine from Suaeda maritima for the treatment of hepatitis.     

Suppressive effect of molybdenum on hepatotoxicity of N-nitrosodiethylamine in rats

SUMMARY

In order to elucidate the preventive mechanism of molybdenum (Mo) against carcinogenesis of N-nitroso compounds, the effects of in vivo Mo-pretreatment on N-nitrosodiethylamine (NDEA)-induced hepatotoxicity in rats were examined. Effects of in vitro Mo-pretreatment on NDEA-induced DNA strand breaks and fluctuation of the cytosolic free Ca levels in rat hepatocytes were also investigated. Male Wistar rats weighing 170–190 g were pretreated with 10 ppm Mo as Na₂MoO₄ in deionized drinking water for 21 days, and on day 22, they were exposed to NDEA (50 mg/kg body weight, once, i.p.). 3 and 5 days after NDEA exposure, serum lactic dehydrogenase (LDH) activity, and hepatic calcium (Ca) content and lipid peroxidation levels were evaluated. In vivo Mo-pretreatment prevented NDEA-induced elevations in serum LDH activity and liver Ca content but increased hepatic lipid peroxidation levels. Hepatocytes isolated from rats pretreated with sodium phenobarbital (80 mg/kg body weight, i.p., once a day for 3 days) were exposed to NDEA (0, 100, 250 and 500 μM) in vitro for 30 min at 37°C. NDEA treatment caused DNA strand breaks and a perturbation of cytosolic free Ca level. However, in vitro Mo-pretreatment (20 μM, 20 min at 37°C) suppressed the NDEA-induced DNA damage and disruption of intracellular Ca homeostasis. These results suggest Mo protected against NDEA-induced hepatotoxicity by stimulating the metabolism of the nitroso compound via a nontoxic pathway (denitration) while preventing DNA damage connected with alteration in cytosolic free Ca levels. Thus, the general protective action of Mo against N-nitroso compound-induced carcinogenesis may be explained by a common mechanism.     

Prevention of chemically induced mammary tumorigenesis by daidzein in pre-pubertal rats: the role of peroxidative damage and antioxidative enzymes

Isoflavones are biologically active plant derived compounds that have several health promoting effects. In the present study hitherto unknown effects of one of the well known isoflavonoids, daidzein, has been evaluated on its chemo-preventive action against breast cancers in pre-pubertal rats. Either daidzein (500 μg/g bwt) or vehicle, dimethyl sulphoxide (DMSO), was administered at 16th, 18th, and 20th day post-partum and the chemopreventive efficacy was evaluated in dimethylbenz[a]nthracene (DMBA) induced Sprague-Dawley rats, at 50th day. To elucidate the mechanism of action, the antioxidative status was also examined in the liver and mammary gland of prebubertal rats using two different doses of daidzein (0.5 mg/kg bwt and 50 mg/kg bwt, p.o.) for 10 days. The specific activity of antioxidant enzymes as well as reduced glutathione (GSH) level and peroxidative damage were evaluated spectrophotometrically, both in liver as well as in mammary gland. Animals treated with daidzein pre-pubertally, showed a significant reduction in the tumorigenesis of mammary gland up to 37.4% as compared to animals induced for tumors with DMBA. In animals treated with 50 mg/kg of daidzein, a significant increase in the specific activities of the antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione transferase (GST), DT-diaphorase (DTD), and in GSH content were observed in both liver and mammary gland. Expectedly, the specific activity of lactate dehydrogenase (LDH) and level of peroxidative damage was decreased, as compared to that of control group of animals. Our results suggest that, daidzein can be considered as a potent chemopreventive agent against mammary carcinogenesis in pre-pubertal animals, with modulation of antioxidant enzymes being one of its mechanisms of actions.