Hepatotoxicity In Rabbits Research Articles

A study of the effect of Nigella sativa (Black seeds) in isoniazid (INH)-induced hepatotoxicity in rabbits

Objective:To investigate the possibility of hepatoprotective effect of Nigella sativa (NS) in INH-induced hepatotoxicity.Materials and Methods:The experiments were carried out on 24 male rabbits. They were divided into 4 groups (6 each); rabbits in group 1 were treated with INH following a standard protocol to induce hepatotoxicity. Rabbits in group 2 received starch. Group 3 received NS 1 g/kg/day before INH treatment. Group 4 rabbits were treated with NS only. Phenobarbital sodium (IP) was given to induce metabolism of INH. INH and NS were given orally. The experiment continued for 12 days; at day 13, animals were sacrificed. Liver function tests, malondialdehyde (MDA) were estimated in serum and in liver homogenates. Liver histopathological examinations were performed.Results:Histopathological changes of hepatotoxicity were found in all INH-treated rabbits. The histopathological findings were normal in three rabbits treated with NS before INH, very mild in two, and with moderate changes in one rabbit. Serum alanine aminotransferase (S.ALT) was elevated after INH treatment and returned back to the control value when NS was given before INH. Similar pattern of effect was noticed with serum aspartate aminotransferase (S.AST), S. total bilirubin, S. MDA, and Serum alkaline phosphatase.In liver homogenate, AST, ALT, and MDA were increased with INH treatment compared to the control, then decreased with NS treatment given before INHConclusions:NS has hepatoprotective effects against INH-induced hepatotoxicity in rabbits. NS 1 g/kg proved safe, no adverse effects; no histopathological or biological abnormalities were seen.

The effect of Hibiscus anthocyanins on 2, 4-dinitrophenylhydrazine-induced hepatotoxicity in rabbits

This study examines the effects of anthocyanin extract of the dried calyces ofHibiscus sabdariffa Linn on the 2, 4-dinitrophenylhydrazine (2, 4-DNPH)-induced toxic side effects in rabbits liver. The side effects of DNPH which include tissue lipid peroxidation and depletion of antioxidant defenses were induced in rabbits with a single intraperitoneal administration of the toxicant (28 mg kg-1 body weight) at the end of a 14-day treatment with Hibiscus anthocyanin extract (100 mg kg-1 body weight twice daily) and after the animals have been fasted overnight. Four hours after the toxicant administration, liver and blood of the experimental animals were analyzed for changes in the activities of hepatic enzyme markers (alanine and aspartate aminotransferases; ALT and AST respectively). The hepatic levels of malondialdehyde (MDA), soluble protein as well as antioxidant molecules, superoxide dismutase (SOD) and reduced glutathione (GSH) were also determined. The anthocyanin extract significantly (p < 0.05) lowered the serum levels of the hepatic enzymes ALT and AST and reduced oxidative liver damage. The extract also significantly counteracted the depleting action of DNPH on the liver protein, SOD and GSH levels. Relative to the DNPH treated group, the extract significantly inhibited the formation of MDA in the liver. The data generated in this investigation show that the anthocyanin extract of H. sabdariffa dried calyces has potent protective properties against 2, 4-dinitrophenylhydrazine-induced oxidative hepatic toxicity in rabbits. Key words: Anthocyanin, antioxidant defenses, 2, 4-dinitrophenylhydrazine, hepatic enzyme markers, Hibiscus sabdariffa, lipid peroxidation.

Therapeutic effect of cimetidine on acetaminophen-induced hepatotoxicity in rabbits

Acetaminophen is a widely used analgesic and antipyretic drug. An overdose can cause life-threatening hepatotoxicity in humans and experimental animals. In this study, 80 female Sprague–Dawley rats randomized into eight groups (three control and five test groups) were used. Three milligrams per kilogram acetaminophen was administered orally to induce liver necrosis. Cimetidine (12.5 mg/kg) was administered intraperitoneally at 0, 1, 2, 4, and 8 h after acetaminophen administration. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and extent of pathologic changes in liver were evaluated in all groups (1–8), and were found to be increased in group 2 (acetaminophen control), but not in groups 1 and 3 (control groups), and were decreased in some treatment groups. The decrease observed in groups 7 and 8 was more than that in group 6. However, in these groups, more animals died due to toxicity before blood sampling. It was concluded that injection of cimetidine 2 h after acetaminophen administration (group 6) can markedly decrease the serum levels of ALT, AST, and the extent of pathologic lesions in the liver with minimal toxicity and death.

Protective effects of vitamin E against CCl4-induced hepatotoxicity in rabbits

AbstractThe influence of CCl4 on the activity of superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), the value of the total antioxidant status (TAS), and the concentration of malonic dialdehyde (MDA) and glutathione (GSH) was monitored in plasma or whole blood of rabbits. The administration of CCl4 caused the increase of the SOD activity to approximately 150 % and the decrease in the activity of GPx and GR by about 50 %. These changes were accompanied with the increase in TAS value and MDA concentration and the decrease of GSH concentration. The effect of CCl4 was suppressed by the previous 7 days lasting or simultaneous administration of vitamin E. Oxidative stress caused by CCl4 was accompanied by the development of reactive oxygen forms, especially superoxide radical anion.

THE ROLE OFl-THYROXINE AND HEPATIC REDUCTASE ACTIVITY IN ISONIAZID-INDUCED HEPATOTOXICITY IN RABBITS

There is evidence that hydrazine, a metabolite of isoniazid, plays an important role in the mechanism of isoniazid-induced hepatotoxicity. Hydrazine has been reported to be metabolised by NADPH cytochrome P-450 reductase (reductase) to reactive and potentially toxic intermediates. The present study was designed, using a model of isoniazid-induced hepatotoxicity in rabbits, to determine whether or not reductase plays a role in this toxicity. Although pretreating rabbits withl-thyroxine increased hepatic reductase activity (54% greater than controls), the severity of isoniazid-induced hepatic cell damage (plasma argininosuccinic acid lyase activity) was lower in thyroxine pre-treated animals than in animals treated with isoniazid alone (31.3±20vs56.0±20 Takahara Units, respectively). In addition, pre-treatment withl-thyroxine completely prevented isoniazid-induced hepatic steatosis. In conclusion, contrary to our hypothesis, an increase in reductase activity achieved by pre-treatment withl-thyroxine was associated with a decrease in the severity of isoniazid-induced hepatic cell damage and steatosis in rabbits.

Isoniazid-induced hepatic necrosis and steatosis in rabbits: absence of effect of gender

Isoniazid, a highly effective drug for the chemoprophylaxis and treatment of tuberculosis, is associated with severe hepatotoxicity in 1-2% of individuals. In a rabbit model of isoniazid-induced hepatotoxicity, we have measured hepatic necrosis (quantitated by elevation of plasma argininosuccinic acid lyase (ASAL) activity), hepatic steatosis (quantitated by elevation of hepatic triglyceride content), and elevation in plasma triglyceride concentration in 15 rabbits. Eight of 15 rabbits were male, and 14 of 15 were rapid acetylators of sulfamethazine. Administration of isoniazid to rabbits resulted in a 27-fold increase in plasma ASAL activities, a 7.5-fold increase in hepatic triglyceride content, and a 13-fold increase in plasma triglyceride levels. This study demonstrated no effect of gender on these three pathological changes that occur in this model of isoniazid-induced hepatotoxicity in rabbits.

Isoniazid-induced hepatic necrosis and steatosis in rabbits: absence of effect of gender

Isoniazid, a highly effective drug for the chemoprophylaxis and treatment of tuberculosis, is associated with severe hepatotoxicity in 1-2% of individuals. In a rabbit model of isoniazid-induced hepatotoxicity, we have measured hepatic necrosis (quantitated by elevation of plasma argininosuccinic acid lyase (ASAL) activity), hepatic steatosis (quantitated by elevation of hepatic triglyceride content), and elevation in plasma triglyceride concentration in 15 rabbits. Eight of 15 rabbits were male, and 14 of 15 were rapid acetylators of sulfamethazine. Administration of isoniazid to rabbits resulted in a 27-fold increase in plasma ASAL activities, a 7.5-fold increase in hepatic triglyceride content, and a 13-fold increase in plasma triglyceride levels. This study demonstrated no effect of gender on these three pathological changes that occur in this model of isoniazid-induced hepatotoxicity in rabbits.

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 (r2 = 0.54, P < 0.002) and log plasma ASAL activity at 48 h after the first dose of INH (r2 = 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.

A model of isoniazid-induced hepatotoxicity in rabbits

Isoniazid (INH) continues to be an effective drug used for chemoprophylaxis and treatment of tuberculosis. Unfortunately, INH is associated with significant hepatotoxicity in up to 2% of individuals exposed, and if this adverse event is not recognized early it can be fatal. Research on INH-induced hepatotoxicity has been hampered by the lack of a suitable animal model that closely resembles the toxicity in humans. The mechanism of INH-induced hepatotoxicity is still unknown. The present study describes the development of a reliable model of INH-induced hepatotoxicity in rabbits. The protocol involves repeated injections of INH over a 2-day period, resulting in significant hepatic necrosis as indicated by elevations of plasma argininosuccinic acid lyase activity. Pretreatment with phenobarbital increased the occurrence of INH-induced hepatic necrosis from approximately 60% (9 out of 15 rabbits) with INH alone to more than 90% (13 out of 14 rabbits). Morphological indices were used to demonstrate the presence of INH-induced hepatotoxicity, and biochemical indices were used to demonstrate both the presence and severity of INH-induced hepatotoxicity in this model. This model may prove useful for further investigations into the mechanism of INH-induced hepatotoxicity.

Oral diclofenac combined with intra-portal pirarubicin: increased efficacy on liver VX2 tumour and hepatotoxicity in rabbits.

VX2 is a carcinoma established in rabbits and producing an autocrine growth factor, prostaglandin E2. Pirarubicin is a potent anti-VX2 agent. We investigated whether the oral intake of enprostil--a synthetic prostaglandin E2--or of diclofenac--a potent non-steroidal anti-inflammatory drug--increases the efficacy and decreases the hepatotoxicity of pirarubicin when injected in the portal trunk. Enprostil increased the number of hepatic tumoral nodules and induced hepatic alterations, especially venous dilatation. Paradoxically the combination of enprostil and pirarubicin was at least as effective as pirarubicin or diclofenac on VX2 cells. However, the toxicity was increased, especially with respect to sclerosing cholangitis. Diclofenac proved to be as effective as pirarubicin, and the addition of oral diclofenac to local pirarubicin injection increased its antitumoral effect (P < 0.02). However, the combination of diclofenac and pirarubicin was more toxic than pirarubicin alone and induced centrolobular necrosis and sclerosing cholangitis.

Blood clearance tests for detecting 2,3,7,8-tetrachlorodibenzo-p-dioxin hepatotoxicity in rats and rabbits.

The objective was to determine if a blood clearance test would detect liver dysfunction in rats and rabbits treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Guinea pigs were included as a negative control, because TCDD does not produce detectable hepatotoxicity in this species. TCDD was given as a single dose to male rats (25 microgram/kg, po), rabbits (25 microgram/kg, ip) and guinea pigs (2 microgram/kg, ip) and liver function was assessed 10 days later by determining blood clearance of indocyanine green (ICG) and ouabain. Activity in serum of sorbitol dehydrogenase (SDH), glutamic pyruvic transaminase (SGPT) and gamma glutamyl transpeptidase (gamma GTP) were also measured and light microscopy performed on the liver. The results showed that hepatotoxicity in the rabbit could be detected by a reduction in ICG blood clearance and an elevation in SDH activity. In the rat, ouabain blood clearance was reduced and SDH activity elevated. None of the liver function tests were altered in the guinea pig. These results underline the usefulness of blood clearance tests using ICG and ouabain in detecting TCDD hepatotoxicity in animals.

Proceedings of the Australasian Society of Clinical and Experimental Pharmacologists

Proceedings of the Australasian Society of Clinical and Experimental Pharmacologists