Effects of Solanum lycopersicum L. (tomato) against isoniazid and rifampicin induced hepatotoxicity in wistar albino rats.

Anti-tuberculosis drugs are reported to cause hepatotoxicity, which varies from asymptomatic rise of the hepatic enzymes. Hepatoprotective plants plays important role to protect liver. This study investigated the hepatoprotective potential of the Solanum lycopersicum in rats intoxicated with Isoniazid and Rifampicin (INH+RIF) to induce hepatotoxicity. Thirty wistar albino rats were divided into five groups of six animals each. Group 1 rats were kept control while groups II, III, IV and V were administered with INH+RIF (75+150 mg/kg) orally, for seven consecutive days. For treatment, rats in group III received silymarin while animals in group IV and V were provided with 40 mg/kg and 80 mg/kg of Solanum lycopersicum extract, respectively. On day 0 and 8th blood samples were collected for the analysis of hepatic biomarkers. The data were subjected to one-way ANOVA and Bonferroni's post hoc test for statistical analysis. Hepatotoxicity induced by INH+RIF resulted in significant elevation of serum hepatic enzymes including Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Alkaline phosphatase (ALP), and total bilirubin while decreased the albumin level. The Solanum lycopersicum at dose of 80 mg/kg significantly reduced the hepatic enzymes AST, ALT, ALP and bilirubin while the albumin level was significantly increased. The treatment had non-significant effect on body and liver weight. Drug induced hepatotoxicity can be effectively treated with Solanum lycopersicum at 80 mg/kg dose.

Ethanolic extract of Mucuna pruriens leaves ameliorates carbon tetrachloride and rifampicin-induced hepatotoxicity and nephrotoxicity in wistar albino rat.

BACKGROUND: Mucuna pruriens (L.) has been used for the treatment of several ailments in folkloric medicine. The present study therefore investigates the hepatoprotective and nephroprotective potentials of its leaves extract with a view to providing a potent alternative in the management of liver and kidney diseases. METHODOLOGY: Forty male albino rats were randomly placed into eight groups comprising five animals each. Animals in group I were administered with the distilled water, while groups II and VI were exposed to CCl4 and rifampicin respectively. Animals in groups III and IV were initially exposed CCl4 and treated with 50 and 100 mg/kg bw M. pruriens respectively. Similarly, groups VII and VIII animals were exposed to rifampicin and treated with 50 and 100 mg/kg bw M. pruriens respectively. Animals in group V were treated with 100 mg/kg bw silymarin by oral gavage after an initial exposure to CCl4. Selected biomarkers of liver and kidney damage were determined in the serum and organs homogenate. Liver and kidney slices of experimental animals were also stained for histopathological examination. RESULTS: Exposure to CCl4 and rifampicin respectively resulted in marked distortion in lipid profile, inhibition of antioxidant enzymes and a surge in ALT, AST, ALP, urea, uric acid, bilirubin and creatine kinase. Treatment with M. pruriens extract reversed all deranged biochemical and histopathological parameters in a dose-dependent manner. CONCLUSION: Extract of M. pruriens leaves restored deranged biochemical and histopathological parameters in the liver and kidney with similar potency to silymarin. Hence, leaf extract of M. pruriens is a potential hepatoprotective and nephroprotective agent that can be exploited in the management of liver and kidney diseases.

The protective effect of lycopene against oxidative kidney damage associated with combined use of isoniazid and rifampicin in rats.

It is known that the combined use of antibiotics, such as isoniazid and rifampicin, in the treatment of tuberculosis causes oxidative kidney damage. The aim of this study was to biochemically and histopathologically investigate the effect of lycopene on oxidative kidney damage due to the administration of isoniazid and rifampicin in albino Wistar male rats. Lycopene at a dose of 5 mg/kg was orally administered to lycopene+isoniazid+rifampicin (LIR) rats, and normal sunflower oil (0.5 mL) was orally administered to isoniazid+rifampicin (IR) and healthy control (HG) rats as vehicle by gavage. One hour after the administration of lycopene and vehicle, 50 mg/kg isoniazid and rifampicin were given orally to the LIR and IR groups. This procedure was performed once a day for 28 days. Rats were sacrificed by a high dose of anesthesia at the end of this period, and oxidant-antioxidant parameters were measured in the removed kidney tissues. Creatinine and blood urea nitrogen (BUN) levels were measured in blood samples, and kidney tissues were also evaluated histopathologically. The combined administration of isoniazid and rifampicin changed the oxidant-antioxidant balance in favor of oxidants, and it increased blood urea nitrogen and creatinine levels, which are indicators of kidney function. Co-administration of isoniazid and rifampicin also caused oxidative kidney damage. Lycopene biochemically and histopathologically decreased oxidative kidney damage induced by isoniazid and rifampicin administration. These results suggested that lycopene may be beneficial in the treatment of nephrotoxicity due to isoniazid and rifampicin administration.

The protective effect of lycopene against oxidative kidney damage associated with combined use of isoniazid and rifampicin in rats

It is known that the combined use of antibiotics, such as isoniazid and rifampicin, in the treatment of tuberculosis causes oxidative kidney damage. The aim of this study was to biochemically and histopathologically investigate the effect of lycopene on oxidative kidney damage due to the administration of isoniazid and rifampicin in albino Wistar male rats. Lycopene at a dose of 5 mg/kg was orally administered to lycopene+isoniazid+rifampicin (LIR) rats, and normal sunflower oil (0.5 mL) was orally administered to isoniazid+rifampicin (IR) and healthy control (HG) rats as vehicle by gavage. One hour after the administration of lycopene and vehicle, 50 mg/kg isoniazid and rifampicin were given orally to the LIR and IR groups. This procedure was performed once a day for 28 days. Rats were sacrificed by a high dose of anesthesia at the end of this period, and oxidant-antioxidant parameters were measured in the removed kidney tissues. Creatinine and blood urea nitrogen (BUN) levels were measured in blood samples, and kidney tissues were also evaluated histopathologically. The combined administration of isoniazid and rifampicin changed the oxidant-antioxidant balance in favor of oxidants, and it increased blood urea nitrogen and creatinine levels, which are indicators of kidney function. Co-administration of isoniazid and rifampicin also caused oxidative kidney damage. Lycopene biochemically and histopathologically decreased oxidative kidney damage induced by isoniazid and rifampicin administration. These results suggested that lycopene may be beneficial in the treatment of nephrotoxicity due to isoniazid and rifampicin administration.

A comparison of hepatoprotective activity of Bacoside to Silymarin treatment against a combined Isoniazid and Rifampin-induced hepatotoxicity in female Wistar rats.

The liver is an important organ that plays a vital role in homeostasis maintenance and regulation. Any liver damage or injury caused by drugs or chemicals is called hepatotoxicity. Isoniazid and rifampin are drugs used separately to treat tuberculosis but have unique side effects and potential hepatotoxicity. The metabolism of isoniazid (INH) and rifampin (RIF) takes place in liver hence hepatotoxicity is the main cause of their continuous use. Bacoside was obtained from the plant Bacopa monnieri, a dammarene type triterpenoid saponin, found distributed throughout India. Bacoside has been used as a nerve tonic, a free radical scavenger, and antioxidant. It is known that the combined INH-RIF induced hepatotoxicity can be antagonized by maintaining hepatocyte membrane integrity in rats. Silymarin, an herbal drug, and its component silybin were reported to work as lipid peroxidation inhibitors and antioxidants which scavenge free radicals. Due to minimal toxicity and no adverse drug interactions, Silymarin is used to treat various medically confirmed hepatic disorders. The aim of this study was to evaluate the beneficial effect of Bacoside against INH- and RIF-induced toxicity in livers of Wistar albino rats. Four experimental groups of rats were used to study four parameters; bodyweight, liver enzyme markers, liver antioxidant, and liver histopathology. INH- and RIF-treated rats showed abnormalities in liver markers which were normalized by Bacoside and that seems similar to the normal control and Silymarin-treated groups. Thus, the current study demonstrated the hepatoprotective effect of Bacoside against INH- and RIF-induced toxicity in Wistar albino rats.

Heterodimeric Rifampicin-Tobramycin conjugates break intrinsic resistance of Pseudomonas aeruginosa to doxycycline and chloramphenicol in vitro and in a Galleria mellonella in vivo model.

Intrinsic resistance in Pseudomonas aeruginosa, defined by chromosomally encoded low outer membrane permeability and constitutively over-expressed efflux pumps, is a major reason why the pathogen is refractory to many antibiotics. Herein, we report that heterodimeric rifampicin-tobramycin conjugates break this intrinsic resistance and sensitize multidrug and extensively drug-resistant P. aeruginosa to doxycycline and chloramphenicol in vitro and in vivo. Tetracyclines and chloramphenicol are model compounds for bacteriostatic effects, but when combined with rifampicin-tobramycin adjuvants, their effects became bactericidal at sub MIC levels. Potentiation of tetracyclines correlates with the SAR of this class of drugs and is consistent with outer membrane permeabilization and efflux pump inhibition. Overall, this strategy finds new uses for old drugs and presents an avenue to expand the therapeutic utility of legacy antibiotics to recalcitrant pathogens such as P. aeruginosa.

Hepatoprotective activity of Tamarindus indica Linn stem bark ethanolic extract against hepatic damage induced by co-administration of antitubercular drugs isoniazid and rifampicin in Sprague Dawley rats.

Background Development of drug-induced hepatic damage (DIHD) during chemotherapy is the most common reason for interruption in chemotherapy. This study evaluated the hepatoprotective activity of the ethanolic extract of Tamarindus indica stem bark (EETI) against the induced DIHD in Sprague Dawley rats. Methods The rats were divided into five groups (n=5). Group I, group III, group IV, and group V rats received 1 mL 1% carboxymethyl cellulose, EETI 100 mg/kg body weight (b.wt), EETI 200 mg/kg b.wt, and silymarin 100 mg/kg b.wt, respectively, orally once every day for 28 days. After 1 h-group II, group III, group IV, and group V rats were administered with isoniazid (INH) and rifampicin (RIF) 50 mg/kg b.wt each orally once every day for 28 days. Then, 24 h after the last dosing, blood was withdrawn from the rats and analyzed for liver specific enzymes and biochemical markers. They were examined for histopathology. Results Co-administration of INH and RIF in group II significantly increased alanine transaminase, aspartate transaminase, alkaline phosphatase, lactate dehydrogenase, serum bilirubin, and cholesterol levels while reduced the total protein and albumin levels compared to that of group I. EETI in group III and group IV rats significantly restored the liver specific enzymes and biochemical markers altered due to co-administration of INH and RIF to normal in a dose-dependent manner. EETI 200 mg/kg b.wt showed better protection to liver than EETI 100 mg/kg b.wt and was comparable to silymarin 100 mg/kg b.wt. It was well supported with histopathology of liver tissues. Conclusions EETI possesses hepatoprotective activity against DIHD in rats. It may have a substantial impact on developing clinical strategies to treat patients with hepatic damage.

Hot aqueous leaf extract of Lasianthera africana (Icacinaceae) attenuates rifampicin-isoniazid-induced hepatotoxicity.

OBJECTIVES: The aim of this study is to evaluate the hepatoprotective effect of Lasianthera africana (Icacinaceae) against isoniazid (INH) and rifampicin (RIF)-induced liver damage in rats. METHODS: The hepatoprotective effects of hot aqueous L. africana (HALA) leaf extract (0.1-1 g/kg) and silymarin (50 mg/kg) were assessed in a model of oxidative liver damage induced by RIF and INH (100 mg/kg each) in Wistar rats for 28 days. Biochemical markers of hepatic damage such as alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) were assessed. The antioxidant statuses of plasma glutathione peroxidase (GSPx), glutathione reductase (GSH), catalase (CAT) and superoxide dismutase (SOD) and lipid peroxidation were evaluated. RESULTS: The pretreatment of INH and RIF decreased hematological indices and the antioxidant levels (P < 0.001) and increased the levels of liver marker enzymes (P < 0.001). However, pretreatment with HALA extract and silymarin provoked significant elevation of hematological indices. The levels of AST, ALT, and ALP were depressed (P < 0.001). Total triglycerides, total cholesterol, total bilirubin and low-density lipoprotein were decreased (P < 0.001). However, high-density lipoprotein, bicarbonate, and electrolytes like chloride and potassium were elevated (P < 0.001), but sodium was depressed (P < 0.05). Additionally, GSH, GSPx, SOD and CAT were elevated (P < 0.01) and malondialdehyde was depressed (P < 0.001) when compared to the RIF-INH-treated rats. Histopathological evaluations support hepatoprotective activity. CONCLUSION: This study demonstrated that HALA leaf extract attenuated RIF-INH-induced hepatotoxicity. L. africana could be exploited in management of RIF-INH-induced hepatitis.

Evaluation of the Protective Role of Glycine max Seed Extract (Soybean Oil) in Drug-Induced Nephrotoxicity in Experimental Rats.

This study was conducted to evaluate the nephroprotective effect of Glycine max seed extract (soybean oil) against gentamicin- and rifampicin-induced nephrotoxicity in Sprague-Dawley rats and to compare its effects with those of vitamin E, which has well-established antioxidant and nephroprotective effects. Sixty male Sprague-Dawley rats (body weight 150-210 g) were divided into 10 groups. The first five groups were treated for 14 consecutive days with normal saline (5 ml/kg, by mouth [p.o.]); gentamicin (80 mg/kg intraperitoneally [i.p.]); gentamicin (80 mg/kg, i.p.) + vitamin E (250 mg/kg p.o.); gentamicin (80 mg/kg i.p.) + soybean oil (2.5 ml/kg p.o.); and gentamicin (80 mg/kg, i.p.) + soybean oil (5 ml/kg p.o.), respectively. For the next five groups, the same group allocation was done, but gentamicin was replaced with rifampicin (1 g/kg i.p.). Various biomarkers for nephrotoxicity in serum and urine were evaluated along with histopathological examination of kidneys. Analysis of variance (ANOVA) was done following Tukey's multiple comparison test; p < .05 was considered significant. Soybean oil in both doses significantly (p < .005) decreased serum blood urea nitrogen, creatinine, urea, uric acid and urine volume, kidney weight, urinary sodium, urinary potassium, and total protein and significantly (p < .005) increased serum total protein and urine creatinine in gentamicin- and rifampicin-treated animals, exhibiting nephroprotective effects. Soybean oil also showed strong antioxidant effects, causing significant (p < .005) increase in kidney homogenate catalases, glutathione peroxidase, and superoxide dismutase and significant (p < .005) decrease in lipid peroxidase in gentamicin- and rifampicin-treated animals. Soybean oil demonstrated good nephroprotective activity due to antioxidant effects.

Adverse effects of anti-tuberculosis drugs on HepG2 cell bioenergetics.

Tuberculosis (TB) is an intractable chronic infection. Disease treatment with anti-TB drugs remains challenging due to drug-induced hepatotoxicity. The toxicity of the anti-TB drugs rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA) either alone or in combination was investigated in HepG2 cells. Assays of intracellular adenosine triphosphate (ATP) levels at 4-, 24- and 48-h post-exposure to gradient concentrations of RIF, INH and PZA were conducted. Drug-induced effects on mitochondrial membrane potential (MMP), mitochondrial complex I and complex III activity, nicotinamide adenine dinucleotide (NAD+) levels and cellular lactate production were assessed. Decreased ATP levels were dose-dependent and correlated with drug exposure duration. Approximate 24-h IC50s were 0.5 mM, 70 mM and 84 mM for RIF, INH and PZA, respectively. Twenty-four hours post-drug treatment, reductions of MMP ( p = 0.0005), mitochondrial complex I and III activities ( p = 0.0001 and p = 0.0003, respectively), NAD+ levels ( p = 0.0057) and increased lactate production ( p < 0.0001) were observed. Drug combinations used to mimic cumulative drug treatments induced a synergistic inhibition of mitochondrial complex I activity. An assessment of cellular ultrastructure using transmission electron microscopy indicated drug-induced mitophagy. Collectively, our study suggests that hepatotoxicity of commonly employed anti-TB drugs is mediated by their curtailment of mitochondrial function.

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.

The food supplement coenzyme Q10 and suppression of antitubercular drug-induced hepatic injury in rats: the role of antioxidant defence system, anti-inflammatory cytokine IL-10.

INTRODUCTION: Isoniazid (INH) and rifampicin (RIF), the most common anti-tubercular therapy, causes hepatotoxicity through a multi-step mechanism in certain individuals. The present study was an attempt to evaluate the hepatoprotective effect of coenzyme Q10 against INH + RIF-induced hepatotoxicity in Wistar albino rats. METHODS: Hepatotoxicity was induced by the oral administration of INH + RIF (50 mg/kg b.w. each/day) in normal saline water for 28 days. The hepatoprotective effect of coenzyme Q10 (10 mg/kg b.w./day) was compared with that of the standard drug silymarin (25 mg/kg b.w./day). Animals were sacrificed at the end of the study period, and blood and liver were collected for biochemical, immunological and histological analyses. RESULTS: Evaluation of biochemical parameters showed that coenzyme Q10 treatment caused significant (P < 0.05) reduction in the elevated levels of serum liver function markers and restored normal levels of total protein, albumin and lipids in INH + RIF-treated rats. Also, it was observed that coenzyme Q10 was able to restore normal levels of enzymic antioxidants, reduced glutathione and lipid peroxidation in the INH + RIF-treated rats. Coenzyme Q10 was found to effectively reduce the extent of liver damage caused due to INH + RIF. In addition, the levels of IL-10 and IL-6 were significantly elevated in the INH + RIF-induced rats treated with CoQ10. CONCLUSION: Our study indicates the protective role of coenzyme Q10 in attenuating the hepatotoxic effects of INH + RIF in a rat model and that it could be used as a food supplement during anti-tubercular therapy.

Hepatoprotective activity of hepatoplus on isonaizid and rifampicin induced hepatotoxicity in rats.

Present study deals with the hepatoprotective activity of polyherbal formulation Hepatoplus (HP) as an oral supplement to the INH and RIF induced hepatitis in experimental rats. Rats treated with INH and RIF show abnormal liver function with significant increase in serum transaminases, bilirubin and clotting time (CT) and significant decrease in total protein and Albumin, which is brings to near normal levels by HP and LIV 52 treatments. Rats treated with INH and RIF suffer from oxidative stress in the hepatocytes, due to the decrease in Glutathione (GSH), Glutathione peroxidase (GPX), Catalase (CAT), Super oxide dismutase (SOD) and significant increase in Lipid Per oxidation (LPO). HP decreases the oxidative stress and protects the liver cells membrane from LPO. 85% of DNA damage (comet tail) seen with RIF and INH treatment is reduced to 34.1% on HP application. A decrease of hepatocytes mitochondrial dehydrogenase activity is observed in INH and RIF treatment is restored by HP supplementation. Hepatic apoptotic and CYP2E1 gene expressions were also studied, BAX, p53, Caspase 3 and CYP2E1 were significantly up regulated and Bcl2 was down- regulated in INH and RIF treated rats. Concomitant application of HP prevents the modulation of these gene expressions. It is concluded that high dose of HP (100mg/kg) supplemented along with INH and RIF effectively prevents the toxicity induced by INH and RIF, as effective as 100mg/kg of LIV52.

Efecto protector del extracto acuoso de las hojas de Peumus boldus Boldo en la toxicidad hepática inducida por rifampicina en ratas Holtzman hembra / Protective effect of aqueous extract of the leaves of Peumus boldus, Boldo, in liver toxicity induced by rifampicin in female Holtzman rats

Objetivo: Determinar el efecto protector del extracto acuoso de las hojas de Peumus boldus "Boldo" en la toxicidad hepática inducida por rifampicina en ratas Holtzman hembra. Materiales y métodos: Se realizó un estudio experimental completo. Se adquirieron 24 ratas Holtzman hembra, y fueron divididas, aleatoriamente, en 4 grupos: A (control), B (rifampicina 100 mg/kg), C (silimarina 200 mg/kg y rifampicina 100 mg/kg) y D (boldo 160 mg/kg y rifampicina 100 mg/kg). Dicho protocolo se realizó por 14 días. Se analizaron variables clínica, bioquímicas (se realizó perfil hepático antes y después del experimento) y morfológica. Se compararon las medias de los grupos mediante la prueba de Kruskall Wallis y se consideró significativo p<0,05. Resultados: Al finalizar el experimento, las ratas del grupo B perdieron más peso (16,41+/-17,94 gr), tuvieron mayor elevación de bilirrubinas totales (0,25+/-0,13), bilirrubina directa (0,21+/-0,12), TGP (48,83+/-17,72) y sus hígados fueron más congestivos, pesaron y midieron más. Las proteínas totales (0,66+/-0,38) y albúmina (0,33+/-0,35) del grupo B fueron menores comparado con los grupos C y D. No se halló diferencia significativa en cuanto a la bilirrubina indirecta, globulina y TGP. Los hígados del grupo B mostraron mayores cambios histopatológicos (5,33+/-0,51) en comparación con los demás grupos. Conclusiones: el extracto acuoso de las hojas de Peumus boldus posee efecto protector en la toxicidad hepática inducida por rifampicina en ratas Holtzman hembra.

Objective: To determinate the protective effect the aqueous extract of the leaves of Peumus boldus "Boldo" on rifampicin-induced liver toxicity in female Holtzman rats. Materials and methods: A complete experimental study was conducted 24 female Holtzman rats were used. They were divided in 4 groups: A (control), B (rifampicin 100 mg/kg), grupo C (silimarina 200 mg/kg and rifampicin 100 mg/kg) y D (boldo 160 mg/kg and rifampicin 100 mg/kg). Rifampicin was administrated one hour after treatment in groups C and D. This protocol was carried out for 14 days. Clinical, biochemical (liver function test were performed before and after the experiment) and morphological variables were analyzed. Means were compared using the Kruskall Wallis test and results were considered significant when p<0.05. Results: At the end of the experiment, rats from group B were the ones who lost more weight, (16.41+/-17.94 g), showed grater elevation of total bilirubin (0.25+/-0.13), direct bilirubin (0.21+/-0.12), TGP (48.83+/-17.72), and whose livers were found to be more congestive, were bigger and weighed more. Whereas leaves of total proteins (0.66+/-0.38) and albumin (0.33+/-0.35) in group B were lower than in other groups. No significant difference was found in levels of indirect bilirubin, globulin and TGO. More intense morphological changes were found in livers of the group B (5.33+/-0.51) compared with other groups. Conclusions: After analyzing clinical, biochemical and morphological parameter, it can be concluded that the aqueous extract of leaves of Peumus boldus has protective effect on rifampicin-induced liver toxicity in female Holtzman rats.

How useful are clinical liver function tests in in vitro human hepatotoxicity assays?

In preclinical hepatotoxicity testing cell based assays are frequently employed. However, prediction of clinical drug induced liver injury (DILI) remains a major challenge. Here we examined the usefulness of frequently employed markers of hepatocellular injury in cultures of primary human hepatocytes (PHH) in response to treatment with either paracetamol, rifampicin, petadolex and/or amiodarone. The changes in the metabolic competency (urea and albumin) and cellular injury (AST, ALT, ALP, LDH, γGT and succinate dehydrogenase) were determined at therapeutic and above drug concentrations as to evaluate the utility of these markers in in vitro systems. Initially, treatment of PHH with any of the drugs caused a statistically significant reduction in enzyme activities to suggest a switch from basic amino acid metabolism towards induced detoxification. However, treatment for prolonged periods of time caused cytolysis, as evidenced by the significant rise in extracellular LDH and the concomitant increase in ALT and AST activity. Notably, amongst the various endpoints studied, urea was best to demonstrate dose dependent metabolic stress, while other markers of hepatocellular injury were highly variable. Taken collectively, urea measurement proofed to be robust in predicting hepatocellular stress; therefore it should be included in preclinical testing strategies for an improved prediction of DILI.

Hepatoprotective potential of Cassia auriculata roots on ethanol and antitubercular drug-induced hepatotoxicity in experimental models.

CONTEXT: Tarvada [Cassia auriculata Linn. (Caesalpiniaceae)] is used against liver ailments in Indian folk medicine, but there is a lack of scientific evidence for this traditional claim. OBJECTIVE: The present study investigated the protective effect of methanol extract of tarvada (MECA) roots on ethanol and antitubercular drug induced hepatotoxicity in rats. MATERIALS AND METHODS: In the therapeutic model, ethanol (40%, 4 g/kg b.w., p.o.) was administered to rats for 21 days and the intoxicated rats were treated with MECA (300 and 600 mg/kg, b.w.) and silymarin (100 mg/kg, b.w.) for next 7 days. In the prophylactic model, MECA and silymarin were administered simultaneously along with a combination of isoniazid (27 mg/kg, b.w.), rifampicin (54 mg/kg, b.w.) and pyrazinamide (135 mg/kg, b.w.) for 30 days. After the study duration, serum levels of AST, ALT, ALP, total bilirubin, total cholesterol, total protein, albumin were estimated along with hepatic catalase (CAT), reduced glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA) and liver histopathology in each group. RESULTS: Administration of tarvada root extract significantly (p < 0.01 and p < 0.05) lowered the elevated levels of serum AST, ALT, ALP, total bilirubin, total cholesterol, total protein and restored the abnormal levels of enzymatic antioxidants and MDA in liver due to toxicant administration in a dose-dependent manner. These results were confirmed by histopathological analysis. DISCUSSION AND CONCLUSION: Results suggest that tarvada root extract possess potent hepatoprotective activity against ethanol and antitubercular drug-induced hepatotoxicity in rats, which could be due to an inhibition of hepatic metabolizing enzymes and antioxidant activity.

Hepatoprotective effects of Yulangsan polysaccharide against isoniazid and rifampicin-induced liver injury in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Yulangsan polysaccharide (YLSPS) is often used in popular folk medicine in the Guangxi Zhuang Autonomous Region of China as a chief ingredient of Millettia pulchra, which is used as an hepatic protection, anti-aging and memory improving agent. In this study, the hepatoprotective effects of YLSPS against isoniazid (INH) or rifampicin and isoniazid (RFP+INH)-induced liver injury were investigated in mice. MATERIALS AND METHODS: The liver injury was induced by intragastric administration of INH or RFP+INH daily for 10 days. During the experiment, the model group received INH or RFP+INH only, and the normal control group received an equal volume of saline. Treatment groups received not only INH or RFP+INH but also the corresponding drugs, DDB (200mg/kg/day) or YLSPS (100, 200, and 400mg/kg/day) 2h after the administration of INH or RFP+INH. RESULTS: Analysis experiments showed that YLSPS significantly alleviated liver injury as indicated by the decreased levels of ALT and AST and the increased levels of SOD, GSH and GSH-Px. Moreover, YLSPS could effectively reduce the pathological tissue damage. The research on the mechanisms underlying the hepatoprotective effect showed that YLSPS was able to reduce lipid peroxidation and activate the anti-oxidative defense system. CONCLUSION: Our results show that YLSPS is effective in attenuating hepatic injury in the INH or RFP+INH-induced mouse model, and could be developed as a new drug for treatment of liver injury.

Hepatoprotective potential of ethanolic extract of Ziziphus oenoplia (L.) Mill roots against antitubercular drugs induced hepatotoxicity in experimental models.

OBJECTIVE: To evaluate the hepatoprotective potential of ethanolic (50%) extract of Ziziphus oenoplia (L.) Mill (Z. oenoplia) root against isoniazid (INH) and rifampicin (RIF) induced liver damage in animal models. METHODS: Five groups of six rats each were selected for the study. Ethanolic extract at a dose of 150 and 300 mg/kg as well as silymarin (100 mg/kg) were administered orally once daily for 21 d in INH + RIF treated groups. The serum levels of glutamic oxaloacetic transaminase (SGOT), glutamate pyruvate transaminase (SGPT), alkaline phosphatase (SALP), and bilirubin were estimated along with activities of superoxide dismutase, catalase, glutathione S-transferase, glutathione peroxidase, and hepatic melondialdehyde formation. Histopathological analysis was carried out to assess injury to the liver. RESULTS: The considerably elevated serum enzymatic activities of glutamic oxaloacetic transaminase, glutamate pyruvate transaminase, alkaline phosphatase and bilirubin due to INH + RIF treatment were restored towards normal in a dose dependent manner after the treatment with ethanolic extract of Z. oenoplia roots. Meanwhile, the decreased activities of superoxide dismutase, catalase, glutathione S-transferase and glutathione peroxidase were also restored towards normal dose dependently. In addition, ethanolic extract also significantly prevented the elevation of hepatic melondialdehyde formation in the liver of INH + RIF intoxicated rats in a dose dependent manner. The biochemical observations were supplemented with histopathological examination of rat liver sections. CONCLUSIONS: The results of this study strongly indicate that ethanolic extract of Z. oenoplia has a potent hepatoprotective action against INH + RIF induced hepatic damage in rats.

Evaluation of antihepatotoxic potential of Solanum xanthocarpum fruit extract against antitubercular drugs induced hepatopathy in experimental rodents.

OBJECTIVE: To assess the hepatoprotective effect of Solanum xanthocarpum (S. xanthocarpum) fruit extract against antitubercular drug-induced liver toxicity in experimental animals. METHODS: Ethanolic (50%) fruit extract of S. xanthocarpum (100, 200 and 400 mg/kg bw) was administered daily for 35 days in experimental animals. Liver toxicity was induced by combination of three antitubercular drugs [isoniazid (I) 7.5 mg/kg, rifampicin (R) 10 mg/kg and pyrazinamide (P) 35 mg/kg] given orally as suspension for 35 days in rats. The hepatoprotective activity was assessed using various biochemical parameters like aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatise (ALP), total bilirubin (TBL), albumin (ALB), total protein (TP), lactate dehydroginase (LDH), and serum cholesterol (CHL). Meanwhile, in vivo antioxidant activities as lipid peroxidation (LPO), reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) were measured in rat liver homogenate. The biochemical observations were supplemented by histopathological examination. RESULTS: The results demonstrated that treatment with S. xanthocarpum significantly (P<0.05-P<0.001) and dose-dependently prevented drug induced increase in serum levels of hepatic enzymes. Furthermore, S. xanthocarpum significantly (up to P<0.001) reduced the LPO in the liver tissue and restored activities of defence antioxidant enzymes GSH, SOD and CAT towards normal levels. Histopathology of the liver tissue showed that S. xanthocarpum attenuated the hepatocellular necrosis and led to reduction in inflammatory cells infiltration. CONCLUSIONS: The results of this study strongly indicate the protective effect of S. xanthocarpum against liver injury which may be attributed to its hepatoprotective activity, and thereby scientifically support its traditional use.

Protective effect of methanolic extract of Annona squamosa Linn in isoniazid-rifampicin induced hepatotoxicity in rats.

The present study was made to investigate the protective effect of methanolic extract of Annona squamosa on isoniazid-rifampicin-induced hepatotoxicity in rats. Rats were divided into five different groups (n=6), group 1 served as a control, Group 2 received isoniazid (100 mg/kg, i.p.) and co-administered with rifampicin (100 mg/kg, i.p.), in sterile water, group 3 and 4 served as extract treatment groups and received 250 & 500 mg/kg bw, p.o methanolic extract of Annona squamosa and group 5 served as standard group and received silymarin 2.5 mg/kg bw, p.o. All the treatment protocols followed 21 days and after rats were sacrificed blood and liver were used for biochemical and histological studies, respectively. Administration of isoniazid and rifampicin caused a significant elevation in the levels of liver marker enzymes and thiobarbituric acid reactive substances (TBARS, oxidative stress markers) in experimental rats. Administration of methanolic extracts of Annona squamosa significantly prevented isoniazid-rifampicin-induced elevation in the levels of serum diagnostic liver marker enzymes (alanine amino transferase (ALT), aspartate amino transferase (AST), alkaline phosphatase (ALP) and gamma glutamate transpeptidase (γ-GT)), serum bilirubin, and TBARS level in experimental groups of rats. Moreover, total protein and reduced glutathione (GSH) levels were significantly increased in treatment group. The effect of extract was compared with a standard drug, silymarin. The changes in biochemical parameters were supported by histological profile. It is to be concluded that the methanolic extract of Annona squamosa protects against isoniazid and rifampicin-induced oxidative liver injury in rats.