Protective Effects of Kaempferol on Isoniazid- and Rifampicin-Induced Hepatotoxicity

Isoniazid (INH) and rifampicin (RIF) are the first-line drugs for antituberculosis (anti-TB) chemotherapy. The levels of serum transaminases [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)] are abnormal in 27% of patients undergoing INH and RIF treatments and in 19% of patients undergoing treatment with INH alone. Cytochrome P450 2E1 (CYP2E1) metabolizes many toxic substrates, including ethanol, carbon tetrachloride, and INH, which ultimately results in liver injury. The objective of this study was to screen for CYP2E1 inhibitors in vitro and investigate whether the selected compound could prevent INH/RIF-induced hepatotoxicity in vivo. We screened 83 known compounds from food and herbal medicines as inhibitors of CYP2E1. The hepatotoxic dose of INH/RIF was 50/100 mg kg⁻¹ day⁻¹. Hepatotoxicity was assessed using galactose single-point (GSP) method (a quantitative measurement of liver function), histopathological examination of the liver, malondialdehyde (MDA) assay, and measurement of AST and ALT activities. Kaempferol inhibited CYP2E1 activity in mice by 0.31- to 0.48-fold (p < 0.005). Mice with INH/RIF-induced hepatotoxicity showed significantly abnormal serum levels of AST and ALT, and GSP value, and these values could be decreased by the administration of kaempferol (p < 0.005). Kaempferol significantly reduced the depletion of hepatic glutathione and prevented the increase in MDA formation in mice. Furthermore, kaempferol did not affect the anti-TB effects of INH/RIF. To our knowledge, this is the first report of kaempferol’s utility as an adjuvant for preventing CYP2E1-mediated hepatotoxicity induced by drugs such as INH and RIF.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-013-9490-6) contains supplementary material, which is available to authorized users.Key words: galactose single-point method, hepatotoxicity, isoniazid, kaempferol, rifampicin     

Monoammonium glycyrrhizinate protects rifampicin- and isoniazid-induced hepatotoxicity via regulating the expression of transporter Mrp2, Ntcp,and Oatp1a4 in liver

Context: Drug-induced liver injury (DILI) is associated with altering expression of hepatobiliary membrane transporters. Monoammonium glycyrrhizin (MAG) is commonly used for hepatic protection and may have a correlation with the inhibition effect of multidrug resistance-associated protein 2 (Mrp2).

Objective: This study evaluates the dynamic protective effect of MAG on rifampicin (RIF)- and isoniazid (INH)-induced hepatotoxicity in rats.

Materials and methods: Male Wistar rats were randomly divided into four groups of 15 rats. Liver injury was induced by co-treatment with RIF (60?mg/kg) and INH (60?mg/kg) by gavage administration; MAG was orally pretreated at the doses of 45 or 90?mg/kg 3?h before RIF and INH. Rats in each group were sacrificed at 7, 14, and 21?d time points after drug administration.

Results: Liver function, histopathological analysis, and oxidative stress factors were significantly altered in each group. The expression of Mrp2 was significantly increased 230, 760, and 990% at 7, 14, and 21 time points, respectively, in RIF- and INH-treated rats. Compared with the RIF and INH groups, Mrp2 was reduced and Ntcp was significantly elevated by 180, 140, and 160% in the MAG high-dose group at the three time points, respectively. The immunoreaction intensity of Oatp1a4 was increased 170, 190, and 370% in the MAG low-dose group and 160, 290, and 420% in the MAG high-dose group at the three time points, respectively, compared with the RIF and INH groups.

Discussion and conclusion: These results indicated that MAG has a protective effects against RIF- and INH-induced hepatotoxicity. The underlying mechanism may have correlation with its effect on regulating the expression of hepatobiliary membrane transporters.     

Effects of N-acetyl cysteine on oxidative stress and TNF-α gene expression in diclofenac-induced hepatotoxicity in rats

The consumption of non-steroidal anti-inflammatory drug, such as diclofenac, can lead to hepatotoxicity. In the present study, protective effect of N-acetyl cysteine (NAC) on diclofenac-induced hepatotoxicity was investigated. Thirty-two male rats were divided into four groups. Group 1 (control group) was treated with normal saline (1?ml/kg, i.p.) for 4?d. Group 2 (test without treatment) received diclofenac only (50?mg/kg, i.p.) for 4?d. Groups 3 and 4 received diclofenac (50?mg/kg, i.p.) plus NAC (150?mg/kg, p.o) and silymarin (100?mg/kg, p.o) for 4?d, respectively. At the end of experiment, serum glutamate pyruvate transaminase (GPT), glutamate oxaloacetate transaminase (GOT), alkaline phosphatase (ALP), lipid profile, uric acid, protein carbonyl content, MDA, liver TNF-α, ferric-reducing antioxidant power, liver catalase, superoxide dismutase, vitamin C, and histopathological examination were done. In group 2, diclofenac caused a significant increase (p?TNF-α gene expression as opposed to group 1. In treated groups with NAC and silymarin, a significant reduction (p?相似文献   

Isoniazid and its toxic metabolite hydrazine induce in vitro pyrazinamide toxicity

Antituberculosis drug-induced hepatotoxicity (ATDH) complicates the treatment of 5–10% of patients treated for active tuberculosis (TB). Knowledge regarding the mechanism of toxicity is still incomplete. Metabolism and the formation of toxic metabolites of the TB drugs may play an important role in the development of ATDH. We studied hepatotoxicity and interactions between isoniazid (INH), its toxic metabolite hydrazine (HYD), rifampicin (RIF) and pyrazinamide (PZA) in human hepatoma cells (HepG2). After 24 h pre-treatment with a non-toxic concentration of one of the four compounds, cells were exposed to increasing concentrations of INH, HYD, RIF or PZA. To determine whether pre-treatment increased toxicity, changes in the concentration at which 50% of cell growth was inhibited (IC₅₀) were quantified using the WST-1 cytotoxicity assay. Pre-treatment with INH, HYD or RIF decreased the INH IC₅₀ by 24%, 26% and 15%, respectively, meaning that INH toxicity was increased. INH and HYD pre-treatment decreased the PZA IC₅₀ by 30% and 38%, respectively. HYD and RIF toxicity were not affected by the pre-treatments. The present study is the first to demonstrate that pre-treatment with INH or its toxic metabolite HYD increases the in vitro toxicity of PZA. In addition, pre-treatment with INH, HYD or RIF increases the in vitro toxicity of INH. These results give us greater insight into the development of ATDH.     

Tournefortia sarmentosa extract attenuates acetaminophen-induced hepatotoxicity

Context: Tournefortia sarmentosa Lam. (Boraginaceae), a Chinese herbal medicine, is commonly used as a detoxicant or anti-inflammatory agent.

Objective: As acetaminophen (APAP) is a well-known hepatotoxin, we investigated the effect of the aqueous extract of the T. sarmentosa on APAP-induced hepatotoxicity in vivo and in vitro.

Materials and methods: Levels of liver function markers serum glutamate oxaloacetate transaminase (SGOT), glutamate pyruvate transaminase (SGPT), and alkaline phosphatase (ALP), inflammatory markers tumor necrosis factor (TNF)-α, interleukin (IL)-1b, and IL-6 in serum, and antioxidant enzymes catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx), as well as lipid peroxidation were determined.

Results: T. sarmentosa significantly reduced the elevated liver function (SGOT, SGPT, and ALP, p?<?0.01) and inflammatory markers (TNF-α, IL-1β, and IL-6, p?<?0.01) in serum of APAP-intoxicated rats. Malondialdehyde level (p?<?0.05) and antioxidant enzyme levels (CAT, SOD, and GPx, p?<?0.05) were also reduced in APAP-intoxicated rats treated with T. sarmentosa. Incubation of rat hepatocyte cell line clone-9 cells with APAP reduced cell viability and increased the extent of lipid peroxidation. APAP stimulation also reduced the level of glutathione (GSH) and caused reduction in the activities of the antioxidant enzymes, CAT, SOD, and GPx. Pretreatment of hepatocytes with T. sarmentosa aqueous extract before and during APAP stimulation attenuated the extent of lipid peroxidation, increased cell viability and GSH level, and enhanced the activities of antioxidant enzymes.

Discussion and conclusion: These data suggest that the aqueous extract of T. sarmentosa can prevent APAP-induced hepatotoxicity.     

Microparticles of rifampicin: comparison of pulmonary route with oral route for drug uptake by alveolar macrophages,phagocytosis activity and toxicity study in albino rats

Abstract

Context: Tuberculosis (TB) is a chronic infectious disease with increasing incidence of drug resistance. Oral treatment for TB and multidrug resistance (MDR)-TB can have serious side effects. The causative agent of TB, Mycobacterium tuberculosis, resides in alveolar macrophages (AM). Pulmonary administration of anti-TB drugs can help in delivery of high concentration to AM. The ability of AM to phagocytose can also be utilized to generate mycobactericidal nitric oxide (NO) to improve efficacy of anti-TB drugs.

Objective: To compare the uptake of rifampicin (RIF) by AM post oral and pulmonary administration of RIF microparticles (RM) and to compare hepatotoxicity and phagocytosis activity.

Materials and Methods: RM were produced by spray drying process. RM were administered to rats through oral as well as intratracheal route. The uptake of RIF by AM and liver was measured. NO was measured in bronchoalveolar lavage (BAL) fluid. SGOT and SGPT levels were measured in serum.

Results: Significantly higher (p?<?0.05) concentration of RIF was found in AM post intratracheal administration. NO production was also significantly higher but less than toxic level. SGOT and SGPT levels as well as uptake of RIF by liver were indicative of no hepatotoxicity post intratracheal administration.

Discussion: Phagocytosis of RM post intratracheal administration leads to significantly higher drug level in AM as well as production of significantly higher levels of NO.

Conclusion: The administration of RM as dry powder inhalation (DPI) formulation may reduce treatment time of TB and chances of drug resistance TB.     

Antioxidant and hepatoprotective effects of Solanum xanthocarpum leaf extracts against CCl4-induced liver injury in rats

Context: Solanum xanthocarpum Schard. and Wendl. (Solanaceae) has been used in traditional Indian medicines for its antioxidant, anti-inflammatory, and antiasthmatic properties.

Objective: The present study demonstrates the antioxidant and hepatoprotective effects of S. xanthocarpum. On the basis of in vitro antioxidant properties, the active fraction from column chromatography of the methanol extract of S. xanthocarpum leaves (SXAF) was chosen as the potent fraction and used for hepatoprotective studies in rats.

Materials and methods: The antioxidant activity was evaluated by 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and reducing power assays. Rats were pre-treated with 100 and 200?mg/kg b.w. of SXAF for 14?d with a single dose of CCl₄ in the last day. Hepatoprotective properties were determined by serum biochemical enzymes, aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), antioxidant enzymes (SOD, CAT, GSH, and GST), and histopathology studies.

Results: SXAF exhibited significant antioxidant activity in scavenging free radicals with IC₅₀ values of 11.72?µg (DPPH) and 17.99?µg (ABTS). Rats pre-treated with SXAF demonstrated significantly reduced levels of serum LDH (1.7-fold), ALP (1.6-fold), and AST (1.8-fold). Similarly, multiple dose SXAF administration at 200?mg/kg b.w. demonstrated significantly enhanced levels of SOD (1.78?±?0.13), CAT (34.63?±?1.98), GST (231.64?±?14.28), and GSH (8.23?±?0.48) in liver homogenates. Histopathological examination showed lowered liver damage in SXAF-treated groups.

Discussion and conclusion: These results demonstrate that SXAF possesses potent antioxidant properties as well as hepatoprotective effects against CCl₄-induced hepatotoxicity.     

Design and evaluation of enteric-coated tablets for rifampicin and isoniazid combinations

In order to improve the bioavailability of rifampicin (RIF) from rifampicin and isoniazid (INH) combination formulations, the physicochemical characteristics of RIF, stability of RIF in different pH buffers in the presence of INH, as well as the effect of particle size of RIF materials on the dissolution rate were investigated. On the basis of the above examinations, enteric-coated tablets for RIF and INH combinations were designed and prepared. RIF showed low solubility and high apparent distribution coefficient in the intestinal pH (pH 4.0–7.4). With the decrease in pH, the degradation of RIF increase and the presence of INH deepen the degradation. Enteric-coated tablets were prepared after grinding the RIF materials by dry granulation technique. The pharmacokinetics of RIF and INH of self-made enteric-coated tablets in dogs were studied by comparing with the reference tablets. The AUC_0–48 of RIF in both reference and test tablets were 304.77 ± 42.27 and 353.79 ± 31.63 µg·h·mL^?1, respectively. The AUC_0–48 of INH in both reference and test tablets were 17.14 ± 8.59 and 19.62 ± 10.57 µg·h·mL^?1, respectively. Enteric-coated tablets may minimize the decomposition of RIF in gastrointestinal tract and improve the bioavailability.     

Hepatoprotective effects of DL-α-lipoic acid and α-Tocopherol through amelioration of the mitochondrial oxidative stress in acetaminophen challenged rats

Abstract

Acetaminophen (APAP) is known to induce liver mitochondrial dysfunction leading to acute hepatotoxicity. Effect of DL-α-lipoic acid (LA) and α-tocopherol (α-Toc) against the APAP-induced liver mitochondrial damage was evaluated in rats. LA (100?mg/kg, p.o.) and α-Toc (100?mg/kg, p.o.) were given once daily for 15?d, prior to the APAP administration (3?g/kg, p.o). Hepatic damage was confirmed by determining the activities of serum glutamate pyruvate transaminase, serum glutamate oxaloacetate transaminase and alkaline phosphatase, 4?h after the single dose of APAP. To assess the mitochondrial damage, the activities of antioxidant enzymes, Krebs’ cycle dehydrogenases and mitochondrial electron transport chain complexes, and levels of reactive oxygen species (ROS), reduced glutathione, lipid peroxidation (malondialdehyde, MDA) as well as the mitochondrial membrane potential (Δψmt) were evaluated. The activities of mitochondrial enzymes and Δψmt were significantly (p?<?0.01) decreased and the level of ROS and MDA were significantly (p?<?0.01) increased due to APAP challenge. LA and α-Toc treatment significantly enhanced the activities of mitochondrial enzymes and Δψmt than that of control group; whereas the levels of ROS and MDA were decreased. The results of the study concluded that the liver damage induced by APAP was significantly ameliorated by LA and α-Toc. LA showed more protection than that of α-Toc. The protection can be partially ascribed to their mitochondrial protective effects through their antioxidant activity which could decrease the level of ROS and by direct enhancement of Δψmt.     

Effect of Curcumin and its Analogue on Lipids in Carbon Tetrachloride–Induced Hepatotoxicity: A Comparative Study

Abstract

Curcumin and its analogue (bis.demethoxy curcumin analogue [BDMC-A]) were studied for their possible lipid-lowering properties in carbon tetrachloride (CCl₄)-induced hepatotoxicity in rats. Carbon tetrachloride (3 ml kg^?1 wk^?1) administration to albino Wistar rats increased the levels of hepatic marker enzymes such as aspartate transaminase (AST), alkaline phosphatase (ALP), and γ.-glutamyl transferase (GGT) in the plasma. The levels of lipids cholesterol, triglycerides, and free fatty acids were also increased in plasma and tissues (liver, kidney, heart, and brain). Phospholipid levels increased in plasma, heart, and brain but decreased in liver and kidney. Curcumin (80 mg/kg) and BDMC-A (80 mg/kg) administration to CCl₄-treated rats for a period of 3 months significantly decreased the lipid levels. The effect exerted by BDMC-A was more prominent than that of curcumin. Studies on the histopathology of the liver are also in line with the biochemical parameters studied. These observations show the lipid-lowering efficacy of curcumin and its analogue in CCl₄-induced hepatotoxicity.     

Isoniazid and rifampicin treatment on phospholipids and their subfractions in liver tissue of rabbits

Although combined treatment of isoniazid (INH) and rifampicin (RIF) has been documented to induce hepatotoxicity and hepatocellular damage, their effect on liver tissue phospholipids is still unknown. Because phospholipids constitute an integral part of hepatocellular membrane, studies were conducted to evaluate the effect of individual and combined treatment of INH and RIF on liver tissue phospholipids in rabbits. Simultaneous administration (i.p.) of INH and RIF (group IV; n = 6), each at a dose of 25 mg/kg for 11 days, caused a significant elevation of phospholipids in plasma from day 5 till day 11. This treatment also caused a significant fall in total inorganic phosphorous, phosphatidylcholine (PC), and cardiolipin (CL) with concomitant increase in phosphatidylethanolamine (PE) and phosphatitylserine (PS) subfractions of phospholipids in the liver tissue of rabbits. Though INH-alone treatment (group II; n = 5) produced a significant fall in total inorganic phosphorous content in the liver tissue, the phospholipid subfractions remain unaltered. RIF-alone treatment (group III; n = 5) did not produce any alteration in phospholipids and their subfractions in liver tissue and plasma of rabbits, and they were comparable to saline-treated control (group I; n = 5). It is likely that simultaneous treatment of INH and RIF could cause choline deficiency, resulting in lowering of phospholipids in the hepatocellular membrane and obstruction of lipoprotein synthesis, culminating in liver injury.     

Antioxidative and Hepatoprotective Effects of Physalis peruviana Extract against Acetaminophen-Induced Liver Injury in Rats

The aim of this study was to examine the antioxidant activities of Physalis peruviana L. (Solanaceae) aqueous extract (PPWE) and its protective effect against acetaminophen (APAP)-induced hepatotoxicity in rats. Using different models of antioxidant assay, namely ferric thiocyanate, 2,2-diphenyl-1-picrylhydrazyl (DPPH), and reducing power, PPWE showed a dose-dependent increase in antioxidant activities, with total antioxidant activity (IC₅₀: 0.81 μ g/ml) close to that of vitamin C (IC₅₀: 0.89 μ g/ml). APAP at 850 mg/kg significantly increased the levels of serum glutamic pyruvic transaminase (sGPT), glutamic oxaloacetic transaminase (sGOT) and alkaline phosphatase (sALP). However, pre-treatment with PPWE at doses 150, 300, and 600 mg/kg body weight significantly prevented the increase in these enzymes, which are the major indicators of liver hepatitis. Biochemical assays of liver homogenate showed that PPWE at 150～ 600 mg/kg significantly enhanced superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) concentrations, and diminished the level of thiobarbituric acid reactive substances (TBARS). Furthermore, liver histological observation also showed an obvious amelioration in the liver cell necrosis, liver lesion, and fatty changes in PP-treated groups. High performance liquid chromatographic analysis showed that ellagic acid (ca. 0.2%) but not others could be the major component contributing to the antioxidant and hepatoprotective activities of PPWE. The present study concludes that PPWE possesses antioxidant activity and potent hepatoprotective effect against APAP-induced liver injury in rats.     

Hepatoprotective and antioxidant effects of gallic acid in paracetamol‐induced liver damage in mice

Objectives The aim of this research paper was to investigate the hepatoprotective and antioxidant effects of gallic acid in paracetamol‐induced liver damage in mice. Methods In the present study, the hepatoprotective and antioxidant effects of gallic acid were evaluated against paracetamol‐induced hepatotoxicity in mice and compared with the silymarin, a standard hepatoprotective drug. The mice received a single dose of paracetamol (900 mg/kg body weight i.p.). Gallic acid (100 mg/kg body weight i.p.) and silymarin (25 mg/kg body weight i.p.) were administered 30 min after the injection of paracetamol. After 4 h, liver marker enzymes (aspartate transaminase, alanine transaminase and alkaline phosphatase) and inflammatory mediator tumour necrosis factor‐alpha (TNF‐α) were estimated in serum, while the lipid peroxidation and antioxidant status (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione‐S‐transferase and glutathione) were determined in liver homogenate of the control and experimental mice. Key findings Increased activities of liver marker enzymes and elevated TNF‐α and lipid peroxidation levels were observed in mice exposed to paracetamol (P < 0.05), whereas the antioxidant status was found to be depleted (P < 0.05) when compared with the control group. However gallic acid treatment (100 mg/kg body weight i.p.) significantly reverses (P < 0.05) the above changes by its antioxidant action compared to the control group as observed in the paracetamol‐challenged mice. Conclusions The results clearly demonstrate that gallic acid possesses promising hepatoprotective effects.     

Isoniazid and rifampicin concentrations in children with tuberculosis with either a daily or intermittent regimen: implications for the revised RNTCP 2012 doses in India

Suboptimal plasma drug concentrations in antitubercular therapy (ATT) may lead to delayed treatment response and the emergence of acquired drug resistance. This study aimed (i) to determine and compare plasma concentrations of isoniazid (INH) and rifampicin (RIF) in children treated for tuberculosis receiving a daily or intermittent ATT regimen and (ii) to study the effect of INH and RIF exposure on clinical outcome at the end of therapy (EOT). A total of 41 children aged 2–16 years initiated on either a daily or three-times weekly (intermittent) ATT regimen were recruited into the study. Towards the end of the intensive phase, blood specimens were collected pre-dose and at 0.5, 1, 1.5, 2, 2.5, 4 and 6?h post-dose. Concentrations of INH and RIF were analysed using validated liquid chromatography–tandem mass spectrometry and high-performance liquid chromatography assays, respectively. The maximum plasma concentration (C_max), the area under the concentration–time curve from 0–6?h (AUC_0–6h) and treatment outcome were determined. Ninety-two percent of patients had an INH C_max?>?3?µg/mL. Seventy-seven percent of patients had a RIF C_max?<?8?µg/mL and 28% of patients had a RIF AUC_0–24h?<?13?mg???h/L. INH and RIF exposure did not differ between daily and intermittent ATT regimens on the day of administration. All children had a favourable outcome at EOT. Since 77% of children had low RIF exposure, we recommend routine use of therapeutic drug monitoring to prevent relapse and to support implementation of the revised RNTCP 2012 doses.     

Role of hydrazine in the mechanism of isoniazid hepatotoxicity in rabbits

 Isoniazid (INH) continues to be a highly effective drug in the chemoprophylaxis and treatment of tuberculosis; however, its use is associated with hepatotoxicity (predominantly hepatic necrosis) in 1–2% of individuals. The INH metabolites, acetylhydrazine and hydrazine, have each been implicated as the causative hepatotoxin in INH-induced hepatotoxicity. Using a model of INH-induced hepatotoxicity in rabbits, in which INH-induced hepatotoxicity manifests as hepatic necrosis, hepatic steatosis (hepatic fat accumulation) and hypertriglyceridaemia (elevated plasma triglycerides), we compared the severity of these measures of toxicity with plasma levels of INH, acetylhydrazine and hydrazine. Plasma INH and acetylhydrazine were not correlated with markers of INH-induced hepatic necrosis or fatty changes. Plasma hydrazine at 32 h was correlated significantly with plasma argininosuccinic acid lyase (ASAL, a sensitive marker of hepatic necrosis) activity as area under the curve (r ²=0.54, P<0.002) and log plasma ASAL activity at 48 h after the first dose of INH (r ²=0.53, p<0.005), but not with fatty changes. These results show in this model of INH-induced hepatotoxicity in rabbits that hydrazine, and not INH or acetylhydrazine, is most likely involved in the pathogenic mechanism of hepatic necrosis. Received: 21 February 1996/Accepted: 30 April 1996     

Role of oxidative stress and nitric oxide in the protective effects of α-lipoic acid and aminoguanidine against isoniazid–rifampicin-induced hepatotoxicity in rats

Despite the great efficacy of isoniazid (INH) and rifampicin (RIF) combination, in the treatment of tuberculosis, hepatotoxicity is the most common serious complication. The potential protective effect of α-lipoic acid and aminoguanidine; against combination-induced hepatotoxicity was investigated in the present study. Administration of INH–RIF combination (50 mg/kg each for 14 days) resulted in an elevation of serum hepatic marker enzymes and a significant increase in lipid profile parameters. Combinations treatment increased lipid peroxidation products, decreased glutathione content, superoxide dismutase, catalase and myeloperoxidase activities. Furthermore, liver total nitrite level was significantly increased in INH–RIF treated rats. Co-administration of either α-lipoic acid or aminoguanidine significantly ameliorate combination-induced alterations in hepatic marker enzymes. These effects were directly linked to a greater decrease in the combination-induced elevation in lipid peroxidation products and total nitrite levels. Furthermore, co-administration of α-lipoic acid and aminoguanidine restore superoxide dismutase, catalase and myeloperoxidase activities and maintained the imbalance in the glutathione level. Additionally, such beneficial effect of α-lipoic acid was linked to a marked lipid-lowering effect. Histopathological examination revealed preservation of liver integrity of the protected groups compared to combination-treated rats alone.     

Effects of phenolic compounds on bromobenzenemediated hepatotoxicity in mice

1. The hepatic protective effects of the phenolic compounds 7,8-dihydroxyflavone, morin, silymarin, caffeic acid and chlorogenic acid on bromobenzene-induced toxicity in mice were studied.

2. Morin, caffeic acid and chlorogenic acid at an oral dose of 200mg/kg failed to influence hepatotoxicity in vivo, while 7,8-dihydroxyflavone exhibited efficacy and potency higher than those of the reference compound silymarin.

3. 7,8-Dihydroxyflavone, an antioxidant and hepatoprotective agent in vitro, decreased serum glutamate-pyruvate transaminase levels (SGPT) in a dose-related manner, and at 200mg/kg inhibited bromobenzene-induced glutathione depletion in liver.     

Bioactive peptide carnosin protects against lead acetate-induced hepatotoxicity by abrogation of oxidative stress in rats

Context Oxidative stress is a common mechanism of liver injury. Carnosine is a dipeptide having strong antioxidant effects.

Objectives We investigated the effects of carnosine on lead-induced hepatotoxicity and oxidative stress in rats.

Materials and methods Animals received an aqueous solution of lead acetate (500?mg Pb/L in the drinking water) and/or daily oral gavage of carnosine (10?mg/kg) for 8 weeks. Rats were then weighed and used for the biochemical (commercial kits), molecular (standard chemical methods) and histological (microscopic) evaluations.

Results Lead-induced oxidative stress in liver tissue was indicated by a significant increase in the level of malondialdehyde (MDA) (8.25?±?0.15?nmol/mg) as well as decrease in the level of total antioxidant capacity (TAC) (1.72?±?0.25?μmol/g) and total thiol (SH) groups) 1.9?±?0.22?μmol/g). Carnosine treatment decreased MDA (4?±?0.08?nmol/mg), whereas it increased the contents of total thiol (3.25?±?0.04?μmol/g) and TAC (3.44?±?0.32?μmol/g) in the lead group. Carnosine also prevented the decreased body weight (p?<?0.001), albumin (p?<?0.05) and total protein levels (p?<?0.001) and increased liver weight (p?<?0.05) and activates of hepatic enzymes (p’s?<?0.001) (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and lactate dehydrogenase) in the lead group. Furthermore, histopathological study showed that carnosine attenuates liver damage by decreasing necrosis and infiltration of inflammatory cells.

Conclusion Carnosine prevented lead-induced hepatotoxicity, indicated by molecular, biochemical and histopathological analyses through inhibiting lipid peroxidation and enhancing antioxidant defence systems. Therefore, carnosine makes a good candidate to protect against the deleterious effect of chronic lead intoxication.     

Influence of silymarin administration on hepatic glutathione-conjugating enzyme system in rats treated with antitubercular drugs

OBJECTIVE: This study evaluated the influence of simultaneous administration of silymarin (SIL), a hepatoprotective and antioxidant agent, on the status of glutathione (GSH) and its metabolising enzymes in the liver tissue of rats treated with antitubercular drugs, i.e. isoniazid (INH), rifampicin (RIF) and pyrazinamide (PYR). METHODS: Male Wistar albino rats (n = 24) were randomly divided into four groups. Group I received saline as they served as controls. Group II rats were administered antitubercular drugs (INH 25 mg/kg + RIF 50 mg/kg + PYR 140 mg/kg orally) daily for 45 days. Group III animals were treated with SIL (50 mg/kg orally) simultaneously with the antitubercular drugs for the same period. Group IV animals were treated with SIL alone. The status of GSH, glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione-s-transferase (GST) in liver tissue was evaluated at the end of the study. RESULTS: Administration of antitubercular drugs caused a significant decrease (p < 0.001) in the status of GPx, GST and GR and of non-enzymic (GSH) antioxidants in liver tissue when compared with saline-treated control rats. Simultaneous treatment of SIL with antitubercular drugs completely prevented decreases in the levels of all the above parameters. Treatment with SIL alone enhanced the activities of GST (p < 0.001) and GPx (p < 0.05) and did not alter glutathione levels compared with control. CONCLUSION: A fall in the status of glutathione and its conjugating enzymes upon administration of antitubercular drugs denotes an impairment of the antioxidant defence mechanism. Simultaneous administration of SIL afforded complete protection of the liver against this abnormality, an effect that could have been due to the strong antioxidant properties of SIL.     

Effect of Spirulina platensis ingestion on the abnormal biochemical and oxidative stress parameters in the pancreas and liver of alloxan-induced diabetic rats

Context: Previous studies have shown that Spirulina platensis Gomont (Phormidiaceae) (SP) extract has beneficial effects on many disease conditions. The putative protective effects of SP were investigated in diabetic rats.

Objective: The current study investigates the antioxidant effects of SP in diabetic Wistar rats.

Materials and methods: Alloxan monohydrate (150?mg/kg body weight) was intraperitoneally administrated to induce diabetes. An aqueous suspension of SP powder in distillate water (10% w/v) was administrated orally by gavage (1?mL/day) for 50?days. Histopathological, biochemical and antioxidant analyses were performed. Glycemia, liver function and HOMA-IR were assessed using Spinreact and ELISA kits.

Results: SP exhibited high-antioxidant activity. The IC₅₀ values of the SP aqueous extract were 70.40 and 45.69?mg/L compared to those of the standard antioxidant BHT, which were 27.97 and 19.77?mg/L, for the DPPH and ABTS tests, respectively. The diabetic animals showed a significant increase in glycaemia (from 4.05 to 4.28?g/L) and thiobarbituric acid reactive substances (50.17?mmol/g protein) levels. Treatment with SP significantly reduced glycaemia by 79% and liver function markers [glutamate pyruvate transaminase (GPT), glutamate oxaloacetate transaminase (GOT) and alkaline phosphatase (Alk-p)]) by 25, 36 and 20%, respectively, compared to that of the controls. There was a significant increase in superoxide dismutase (48%), total antioxidant status (43%), glutathione peroxidase (37%) and glutathione reductase (16%) in the diabetic rats treated with SP.

Discussion and conclusion: These results showed that SP has high antioxidant activity, free radical scavenging, antihyperglycemic and hepatoprotective effects in diabetes.