Hepatotoxicity In Male Wistar Rats Research Articles

Camellia sinensis and epicatechin abate doxorubicin-induced hepatotoxicity in male Wistar rats via their modulatory effects on oxidative stress, inflammation, and apoptosis

This study aimed to assess the preventive effects of Camellia sinensis (green tea) leaf aqueous extract and epicatechin and to scrutinize their possible mechanisms of action in doxorubicin-induced liver injury. Phytochemical screening of Camellia sinensis aqueous extract was performed by LC/ESI-MS/MS that revealed the presence of epicatechin and other polyphenols. Male Wistar rats were intraperitoneally injected with doxorubicin (4 mg/kg/week) and were orally treated with Camellia sinensis aqueous extract (200 mg/kg) or epicatechin (25 mg/kg) every other day for 6 weeks. The treatments of doxorubicin-injected rats with the extract and epicatechin resulted in a marked amelioration of the deteriorated effects on albumin, AFP and total bilirubin levels as well as ALT, AST, ALP and GGT activities. The treatments also alleviated the altered serum TNF-α and IL-4, liver LPO and GSH levels as well as liver SOD, GPx and GST activities. In association, the expression of liver NF-κB, COX-2, p53 and caspase-3 was remarkably decreased, the expression of Bcl-2 was significantly increased, and the liver histological architecture were remarkably amended by treatments. Camellia sinensis aqueous extract and epicatechin may have effective chemopreventive potentials against doxorubicin-induced hepatotoxicity via reinforcement of antioxidant defense system and attenuation of the inflammatory and apoptotic effects.

The Preventive Effects and the Mechanisms of Action of Navel Orange Peel Hydroethanolic Extract, Naringin, and Naringenin in N-Acetyl-p-aminophenol-Induced Liver Injury in Wistar Rats.

N-Acetyl-p-aminophenol (APAP) or acetaminophen is the most common drug ingredient worldwide. It is found in more than 600 different over-the-counter and prescription medicines. Its long-term and overdose use is highly toxic and may result in liver injury. Thus, this study was designed to assess the preventive effects and to suggest the mechanisms of action of the navel orange peel hydroethanolic extract, naringin, and naringenin in APAP-induced hepatotoxicity in male Wistar rats. APAP was administered to male Wistar rats at a dose level of 0.5 g/kg body weight (b.w.) by oral gavage every other day for 4 weeks. APAP-administered rats were treated with the navel orange peel hydroethanolic extract (50 mg/kg b.w.), naringin (20 mg/kg b.w.), and naringenin (20 mg/kg b.w.) by oral gavage every other day during the same period of APAP administration. The treatments of APAP-administered rats with the peel extract, naringin, and naringenin produced a significant decrease in the elevated serum AST, ALT, ALP, LDH, and GGT activities as well as total bilirubin and TNF-α levels while they induced a significant increase in the lowered serum albumin and IL-4 levels. The treatments also resulted in a significant decrease in the elevated liver lipid peroxidation and enhanced the liver GSH content and SOD, GST, and GPx activities as compared with APAP-administered control; the peel extract was the most potent in improving the liver LPO, GSH content, and GPx activity. In addition, the three treatments significantly downregulated the elevated hepatic proapoptotic mediators p53, Bax, and caspase-3 and significantly upregulated the suppressed antiapoptotic protein, Bcl-2, in APAP-administered rats. In association, the treatments markedly amended the APAP-induced liver histopathological deteriorations that include hepatocyte steatosis, cytoplasmic vacuolization, hydropic degeneration, and necrosis together with mononuclear leucocytic and fibroblastic inflammatory cells' infiltration. In conclusion, the navel orange peel hydroethanolic extract, naringin, and naringenin may exert their hepatopreventive effects in APAP-administered rats via enhancement of the antioxidant defense system and suppression of inflammation and apoptosis.

Ganoderic acid -loaded solid lipid nanoparticles ameliorate d-galactosamine induced hepatotoxicity in Wistar rats

Ganoderic acid has been known as a key bioactive constituent in Ganoderma lucidum, commonly used for preventing and treating hepatopathy of various etiologies. This study was designed to investigate the hepatoprotective and antioxidant activity of ganoderic acid loaded solid lipid nanoparticles in d-galactosamine induced hepatotoxicity in male Wistar rats. Ganoderic acid loaded solid lipid nanoparticles was prepared by solvent injection technique and prepared formulation was characterized for various parameters and final formulation evaluated for its hepatoprotective study in Wistar rats. The prepared optimized formulation presented particle size of 122.7 ± 8.6 nm with polydispersity index of 0.27 ± 0.03 and zeta potential of −18 ± 1.4 mV. The drug loading, entrapment efficiency and nanoparticle yield were found to be 21.6 ± 1.23%, 70.16 ± 3.21% and 60.5 ± 2.75%, respectively. In vitro release study of ganoderic acid from nanoparticles at pH 7.4 exhibited biphasic release pattern with an initial burst release followed by a sustained release. Treatment of rats with prepared formulation significantly restored the levels of serum hepatic markers and antioxidant enzymes as compared to free ganoderic acid in d-galactosamine induced hepatotoxicity in rats. Histopathological examination also supported a marked hepatoprotective effect of prepared formulation. In conclusion, nano-formulation of ganoderic acid has significantly attenuated markers of hepatic damage compared to free ganoderic acid and may represent a potential hepatoprotective nano-formulation for amelioration of d-galactosamine induced liver injury.

Omega-3 fatty acids moderate oxidative and proinflammatory events in experimental hepatotoxicity in Wistar rats: comparison with livolin

Dietary supplementation with omega-3 fatty acids have been advocated because of the global preference for the omega-6 fatty acids - rich Western style diet. The study investigated the effects of omega-3 fatty acids (combination of N-3: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA); EPA/DHA ratio = 3/2) compared to livolin (Phosphatidylcholin + vitamins) on biochemical and haematological parameters in diclofenac (DF) - induced hepatotoxicity in male Wistar rats. Twenty five rats were used. They were divided into 5 groups (n = 5) which included: Group 1-Control (untreated); Group 2-DF control; Group 3-DF + Low N-3; Group 4-DF+High N-3; and, Group 5-DF + Livolin. Group 2 received DF at 10 mg/kg b.w. (i.m.) during the first 7days of the experiment, thereafter; they were administered distilled water (0.1 ml) for three weeks. Groups 3, 4, and 5 were pre-treated with DF during the first 7days of the experiment, afterwards, they were post-treated with N-3 and livolin at 100, 300, and 5.2 mg/kg b.w. (p.o.) respectively for 21days.The results showed that DF caused significant increases in MDA, LDH, proinflammatory markers, ALT, AST, and ALP activities, but, significant decreases in antioxidant indices. However, post-treatment with N-3 or livolin corrected these deviations. Although there was evidence of the dose dependent effects of N-3, the high dose was not always the most effective. The histological results proved that livolin has a more hepatoprotective action than N-3, although the biochemical and haematological findings attested that both therapies have comparable effects. It was concluded that livolin proffers a more protective effect than N-3 in DF-induced hepatotoxicity.

Effects of rosmarinic acid on acetaminophen-induced hepatotoxicity in male Wistar rats

Context: Drug-induced liver injury is a significant worldwide clinical problem. Rosmarinic acid (RA), a natural phenol, has antioxidant effects. Objective: The effects of RA against acetaminophen (N-acetyl-p-amino-phenol (APAP))-induced oxidative damage and hepatotoxicity in rats were investigated. Materials and methods: Male Wistar rats were pretreated with RA (10, 50 and 100 mg/kg, i.g.) for one week. On day 7, rats received APAP (500 mg/kg, i.p.). Then aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, total protein, malondialdehyde (MDA), glutathione (GSH), total antioxidant capacity (TAC), glutathione S-transferase (GST), cytochrome CYP450 and histopathological changes were determined. Results: APAP-induced oxidative stress in liver by a significant increase in the level of MDA (7.6 ± 0.21 nmol/mg) as well as a decrease in the contents of TAC (1.75 ± 0.14 μmol/g), GSH (1.9 ± 0.22 μmol/g) and GST) 3.2 ± 0.28 U/mg). RA treatment decreased MDA (4.32 ± 0.35 nmol/mg) but increased the contents of TAC (3.51 ± 0.34 μmol/g), GSH (3.42 ± 0.16 μmol/g) and GST (5.71 ± 0.71 μmol/g) in APAP group. RA 100 mg/kg decreased ALT (91.5 ± 1.5 U/L), AST (169 ± 8.8 U/L) and CYP450 (3 ± 0.2 nmol/min/mg) in APAP group. Histologically RA attenuated hepatic damage by decreasing necrosis, inflammation, and haemorrhage in liver sections of APAP group. Discussion and conclusions: This is the first report that oral administration of RA dose-dependently elicited significant hepatoprotective effects in rats through inhibition of hepatic CYP2E1 activity and lipid peroxidation. RA-protected hepatic GSH and GST reserves and total tissue antioxidant capacity.

Allium cepa Mitigates Aluminum Chloride-Induced Hepatotoxicity in Male Wistar Rats

Allium cepa (Common Onion), one of the most widely grown crops in world, is believed to possess medicinal potency. The present study was designed to investigate the effect of Allium cepa (ACE) administration on oxidative stress-mediated hepatotoxicity following aluminum chloride (AlCl3) administration. 24 adult male wistar rats weighing 175 g were randomly divided into vehicle-treated (control), ACE, aluminum chloride (AlCl3) and ACE+AlCl3 groups. Rats were given single oral administrations of 100mg/kg body weight of AlCl3 and 1 mL/0.1 kg body weight of ACE for four weeks. When compared with vehicle-treated, AlCl3 administration caused a significant decrease in serum total protein (TP) and an increase in serum levels of alanine transaminase (ALT), aspartate transaminase (AST) and total bilirubin. On the other hand, ACE treatment significantly improved serum TP but depressed serum levels of ALT, AST and total bilirubin. There was no significant change in these biomarkers of liver function in ACE+AlCl3 group compared with the vehicle-treated group. Furthermore, while AlCl3 group was characterized by a significant rise in hepatic malondialdehyde (MDA) and a decrease in hepatic superoxide dismutase (SOD) and catalase activities, ACE group exhibited a significant low hepatic MDA and a high hepatic SOD and catalase activities. However, none of these antioxidant markers changed in ACE+AlCl3 group compared with vehicle-treated. Therefore, we conclude that ACE mitigates hepatotoxic effect of AlCl3 administration through regulation of hepatic oxidant/antioxidant system.

Methanol Extract of Adansonia digitata Leaf Protects Against Sodium Arsenite-induced Toxicities in Male Wistar Rats.

Background:Human and animal population exposure to arsenic through the consumption of arsenic contaminated water is rampant in many parts of the world. Protective agents of medicinal plants origin could provide maximum protection against toxicities of various kinds.Objective:The protective role of orally administered methanol extract of the leaves of Adansonia digitata (MELAD) on sodium arsenite (SA) – induced clastogenicity and hepatotoxicity in male Wistar rats was evaluated.Materials and Methods:Thirty male Wistar rats divided into six Groups (1–6) of five animals each were used for the study. Group 1 (negative control) received distilled water and normal diet only, Groups 2–6 received the extract (at 250 or 500 mg/kg body weight) and/or SA at 2.5 mg/kg body weight.Results:There was statistically significant (P < 0.05) increase in the number of micronucleated polychromatic erythrocytes and lipid peroxidation in the SA group as compared with the negative control and treated groups. Administration of the extract reduced the effects of SA on the above parameters. Activities of serum alanine and aspartate aminotransferases did not show statistically significant effects; however, the histological analyses revealed periportal cellular infiltration by mononuclear cells, whereas the MELAD treated groups show mild cellular infiltration and mild portal congestion.Conclusions:MELAD protect against SA-induced toxicities in rats, and it may offer protection in circumstances of co-exposure and cases of arsenicosis.SUMMARY MELAD extract significantly reduce the lipid peroxidation induced by sodium arsenite in the liver of rats.MELAD did not show profound effects on the activities of serum alanine (ALT) and aspartate (AST) aminotranferases.MELAD offered significant protection against sodium arsenite-induced genotoxicity in the micronuclei induction assay.In the circumstances of co-exposure to arsenic contamination, MELAD may protect against sodium arsenite-induced toxicities. Abbreviations Used: MELAD: Methanol extract of the leaves of Adansonia digitata, SA: Sodium arsenite, nMPCEs: Number of micronucleated polychromatic erythocytes; ALT: Alanine aminotranferase; AST: Aspartate aminotranferase, TBARS: Thiobarbituric acid reactive substances, TBA: Thiobarbituric acid, MDA: malondialdehyde, Sodium arsenite (NaAsO2), IARC: International Agency for Research on Cancer

Malathion-induced hepatotoxicity in male Wistar rats: biochemical and histopathological studies.

The increasing use of organophosphorus pesticides in the environment constitutes an ecotoxicological hazard especially for humans and non-target animals. Hereby, we analyzed the toxic effects of malathion on the histological structure of liver and biochemical parameters in male rats. Three groups received daily different amounts of malathion: 1/1000, 1/100, and 1/10 LD50 for 30 days. The weights of treated rat's liver have increased. Analyzed tissues showed centrilobular and sinusoidal congestion, hepatocyte hypertrophy, cellular vacuolization, anucleated hepatocytes, depletion of organelles affecting the majority of cells, and presence of necrotic foci into the hepatic parenchyma. Histological sections of the liver showed important hepatocyte glycogen storage. We conclude that malathion stimulates the filing of glycogen in a dose-dependent manner. Biochemical parameters showed that alanine transaminase (ALT), aspartate transaminase (AST), gamma glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH), and alkaline phosphatase (ALP) levels increased in the treated groups when the level of total protein decreased in intoxicated groups.

Genistein modulates the expression of NF-κB and MAPK (p-38 and ERK1/2), thereby attenuating d-Galactosamine induced fulminant hepatic failure in Wistar rats

Genistein is an isoflavanoid abundantly found in soy. It has been found to play an important role in the prevention of various chronic diseases including cancer. In this study, we evaluated potential therapeutic properties of Genistein against d-Galactosamine (d-GalN) induced inflammation and hepatotoxicity in male Wistar rats. Fulminant hepatic failure (FHF) was induced in rats by intraperitoneal injection of d-GalN (700mg/kgBW). Genistein (5mg/kgBW/day) was given as pre-treatment for 30days via intra-gastric route followed by d-GalN (700mg/kgBW) injection. The hepatoprotective and curative effects of Genistein were evident from a significant decrease in the serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels as well as prevention of histological damage by pre-treatment of Genistein. Genistein pre-treatment significantly inhibited the increased protein levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), thereby reducing nitric oxide (NO) and prostaglandin-E2 (PGE) levels, respectively. In addition Genistein significantly suppressed the production of d-GalN-induced proinflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin (IL)-1β. These inhibitory effects were associated with the suppression of nuclear factor-kappa B (NF-ĸB) activation, IKKα/β and Mitogen activated protein kinase (MAPK) phosphorylation by Genistein in d-GalN-treated animals. In conclusion, our results suggest that Genistein may serve as a potential supplement in the prevention of hepatic and inflammatory diseases. Furthermore Genistein is able to maintain the redox potential and strengthens the antioxidant defense system of a cell.

Alleviation of doxorubicin-induced nephrotoxicity and hepatotoxicity by chrysin in Wistar rats

Objective: Doxorubicin (DXR) is an anticancer drug used in the treatment of many human malignancies. However, its clinical use is limited because of several side effects like cardiotoxicity, nephrotoxicity and hepatotoxicity. In the present study, we investigated the protective efficacy of chrysin against DXR-induced oxidative stress, nephro- and hepatotoxicity in male Wistar rats using biochemical and histopathological approaches.Methodology: Wistar rats were subjected to concomitant pre- and post-phylactic oral treatment of chrysin (40 and 80 mg/kg b.wt.) against nephro- and hepatotoxicity induced by single i.p. injection of DXR (40 mg/kg b.wt). Nephrotoxicity and hepatotoxicity were assessed by measuring the level of serum creatinine, BUN, AST, ALT and LDH. The level of antioxidant armory of kidney and liver tissue was also measured.Key findings: Treatment with chrysin significantly decreased the levels of serum toxicity markers and additionally elevated antioxidant defense enzyme levels. Histopathological changes further confirmed the biochemical results showing that DXR caused significant structural damage to kidney and liver tissue architecture which were reversed with chrysin.Conclusion: The results suggest that chrysin attenuated nephro and hepatic damage induced by DXR.

Ferulic Acid Modulates Fluoride-Induced Oxidative Hepatotoxicity in Male Wistar Rats

The present study is aimed to evaluate the protective effect of ferulic acid (FA) on fluoride-induced oxidative hepatotoxicity in male Wistar rats. Fluoride (25 mg/L) was given orally to induce hepatotoxicity for 12 weeks. Hepatic damage were assessed using status of pathophysiological markers like serum marker enzymes like aspartate transaminase, alanine transaminase, alkaline phosphatase, acid phosphatase, gamma glutamyl transferase, lactate dehydrogenase, bilirubin, lipid profile, total protein content levels, and histopathological studies. Treatment with FA significantly reduced the degree of histological aberrations and rescued lipid peroxidation, as observed from reduced levels of lipid hydroperoxides, nitric oxide, restored levels of enzymic and non-enzymic antioxidants, and total protein content, with a concomitant decline in the levels of marker enzymes and lipid profile in fluoride-induced rats. These results suggest that ferulic acid has the ability to protect fluoride-induced hepatic damage.

Protective Role ofFicus caricaStem Extract against Hepatic Oxidative Damage Induced by Methanol in Male Wistar Rats

The present study was aimed to investigate the antioxidant activity of Ficus carica stem extract (FE) in methanol-induced hepatotoxicity in male Wistar rats. The rats were divided into two batches: 16 control rats (C) drinking tap water and 16 treated rats drinking Ficus carica stem extract for six weeks. Then, each group was divided into two subgroups, and one of them was intraperitoneally injected (i.p.) daily methanol at a dose of 2.37 g/kg body weight i.p. for 30 days, for four weeks. The results showed that FE was found to contain large amounts of polyphenols and carotenoids. The treatment with methanol exhibited a significant increase of serum hepatic biochemical parameters (ALT, AST, ALP, and LDH) and hepatic lipid peroxidation. Hepatic antioxidant enzymes, namely, SOD, CAT, and GSH-Px, were significantly decreased in methanol-treated animals. FE treatment prior to methanol intoxication has significant role in protecting animals from methanol-induced hepatic oxidative damage.

Hesperetin protects against oxidative stress related hepatic dysfunction by cadmium in rats

The present study was to evaluate the hepatoprotective effect of hesperetin (HTN) on cadmium (Cd) induced hepatotoxicity in male Wistar rats. Administration of Cd (3 mg/kg body weight/day) subcutaneously for 21 days, the levels of hepatic markers such as aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), gamma glutamyl transferase (GGT) and bilirubin were significantly increased in serum. The levels oxidative stress markers, thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (LOOH), conjugated dienes (CD) and protein carbonyl content (PCC) were also significantly increased while the levels of vitamin C, vitamin E, reduced glutathione (GSH), total sulphydryl group (TSH) and the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST), glutathione reductase (GR) and glucose-6-phosphate dehydrogenase (G6PD) were significantly decreased in the liver of Cd intoxicated rats. HTN, a flavanone in citrus fruits, administrated orally along with Cd injection for 21 days, significantly revert back the status of serum hepatic markers, oxidative stress markers and antioxidant markers in the liver tissue to near normal level in a dose dependent manner. HTN at a dose of 40 mg/kg body weight/day exhibits significant (p<0.05) hepatoprotection compared with other two doses (10 and 20 mg/kg body weight/day). The histopathological studies in the liver of rats also supported that HTN (40 mg/kg) markedly reduced the toxicity of Cd and preserved the histoarchitecture of the liver tissue to near normal. Thus, the results suggest that HTN acts as a potent hepatoprotective agent against Cd induced hepatotoxicity in rats.

Hepatoprotective activity of ethanolic extracts of bark of Zanthoxylum armatum DC in CCl 4 induced hepatic damage in rats

Aim of the study Zanthoxylum armatum DC is described as a hepatoprotective in Ayurveda, the Indian system of medicine. However, there is no scientific basis or reports in the modern literature regarding its usefulness as a hepatoprotective agent. The present study was carried out to evaluate the hepatoprotective activity of ethanolic extract of bark of Zanthoxylum armatum DC in CCl 4 induced hepatotoxicity in male Wistar rats. Materials and methods Ethanolic extracts at doses of 100, 200, and 400 mg/kg were administered orally once daily for 7 days. The hepatoprotective activity was assessed using various biochemical parameters like alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, serum bilirubin, total protein and serum antioxidant enzymes along with histopathological studies of liver tissue. Results The substantially elevated serum enzymatic levels of serum transaminases, alkaline phosphatase and total bilirubin were significantly restored towards normalization by the extracts. Bark extracts significantly increased the levels of antioxidant enzymes: superoxide dismutase, catalase and glutathione. Phytochemical analysis revealed presence of isoquinoline alkaloid, berberine, as well as flavonoids and phenolic compounds, which have been known for their hepatoprotective activities. Conclusions Zanthoxylum armatum DC possesses significant protective effect against hepatotoxicity induced by CCl 4 which may be attributed to the individual or combined action of phytoconstituents present in it.

Potentiation of aflatoxin B1 induced hepatotoxicity in male Wistar rats with ethanol pretreatment.

The interaction of ethanol and aflatoxin B1 (AFB1)-induced hepatotoxicity was studied in male Wistar rats using the activity of plasma GOT and GPT, liver triglyceride and histopathologic changes of liver necrosis as indices. Pretreatment of four oral doses of ethanol (4.0 g/kg BW each) at 48, 45, 24 and 21 hrs prior to AFB1 (0.5 to 2.0 mg/kg BW) single i.p. administration caused a significant increase in the activity of PGOT (6 folds) and PGPT (5 folds), liver triglycerides (2 folds) and severity of liver necrosis at 48 hrs after AFB1 administration. Ethanol pretreatment potentiated AFB1-induced hepatotoxicity by increasing MFO enzymes, aniline hydroxylase and p-nitroanisole-O-demethylase activity and lipid peroxidation, and decreasing in cytochrome b5, epoxide hydrolase activity and hepatic glutathione content. However, it did not cause any significant change in the activity of NADPH-cytochrome c reductase and glutathione-S-transferase and cytochrome P-450. These results suggest that potentiation of ethanol pretreatment on AFB1-induced hepatotoxicity may be due to an increase in the metabolic formation of AFB1-2, 3-oxide and subsequent binding to DNA.