rehmannic-acid and Chemical-and-Drug-Induced-Liver-Injury

The hepatoprotective effect of freeze-dried methanolic leaf extract of Ginkgo biloba was evaluated against lantadenes-induced hepatic damage in guinea pigs. The reversed-phase HPLC analysis of lantadenes confirmed the presence of 72.82% of lantadene A. UPLC-ESI-MS analysis showed the presence of ginkgolide B, C, bilobalide and traces of ginkgolide A and J in G. biloba extract. The concentration of ginkgolide B in the sample was found as 0.29%. The elevated levels of serum alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase due to lantadenes were significantly restored towards normal values by G. biloba extract in a dose-dependent manner. The effects of lantadenes and G. biloba extract on lipid peroxidation (LPO), reduced glutathione (GSH), superoxide dismutase (SOD) and catalase were assayed in liver homogenates to evaluate the antioxidant activity. G. biloba extract in a dose-dependent manner produced significant decrease in lantadenes-induced increased levels of LPO. The lantadene-induced decreased levels of SOD, GSH and catalase were elevated by G. biloba extract. The findings of biochemical and antioxidant enzyme levels were supported by gross and histopathological observations. Moreover, liver sections of G. biloba group also showed a marked decrease in apoptosis in comparison to lantadenes group. This study suggested that G. biloba could be used as a promising hepatoprotectant against lantadenes-induced hepatic damage. Future studies are needed to elucidate the precise mechanism of hepatoprotection for practical application.

Topics: Animals; Apoptosis; Catalase; Chemical and Drug Induced Liver Injury; Ginkgo biloba; Glutathione; Guinea Pigs; Lipid Peroxidation; Liver; Oleanolic Acid; Oxidative Stress; Plant Extracts; Protective Agents; Superoxide Dismutase; Toxins, Biological

The aim of the present study was to evaluate the hepatoprotective activity of lantadene A against acetaminophen-induced liver toxicity in mice was studied. Activity was measured by monitoring the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and bilirubin, along with histo-pathological analysis. Silymarin was used as positive control. A bimodal pattern of behavioural toxicity was exhibited by the lantadene A-treated group at the beginning of the treatment. However, treatment with lantadene A and silymarin resulted in an increase in the liver weight compared with the acetaminophen treated group. The results of the acetaminophen-induced liver toxicity experiments showed that mice treated with lantadene A (500 mg/kg) showed a significant decrease in the activity of ALT, AST and ALP and the level of bilirubin, which were all elevated in the acetaminophen treated group (p < 0.05). Histological studies supported the biochemical findings and a maximum improvement in the histoarchitecture was seen. The lantadene A-treated group showed remarkable protective effects against histopathological alterations, with comparable results to the silymarin treated group. The current study confirmed the hepatoprotective effects of lantadene A against the model hepatotoxicant acetaminophen, which is likely related to its potent antioxidative activity.

Topics: Acetaminophen; Alanine Transaminase; Alkaline Phosphatase; Animals; Aspartate Aminotransferases; Bilirubin; Chemical and Drug Induced Liver Injury; Humans; Lantana; Liver; Mice; Oleanolic Acid; Plant Leaves; Protective Agents; Silymarin

Lantana (Lantana camara Linn.) is a noxious weed to which certain medicinal properties have been attributed, but its ingestion has been reported to be highly toxic to animals and humans, especially in the liver. The main hepatotoxin in lantana leaves is believed to be the pentacyclic triterpenoid lantadene A (LA), but the precise mechanism by which it induces hepatotoxicity has not yet been established. This work addressed the action of LA and its reduced derivative (RLA) on mitochondrial bioenergetics. At the concentration range tested (5-25 microM), RLA stimulated state-4 respiration, inhibited state-3 respiration, circumvented oligomycin-inhibited state-3 respiration, dissipated membrane potential and depleted ATP in a concentration-dependent manner. However, LA did not stimulate state-4 respiration, nor did it affect the other mitochondrial parameters to the extent of its reduced derivative. The lantadenes didn't inhibit the CCCP-uncoupled respiration but increased the ATPase activity of intact coupled mitochondria. The ATPase activity of intact uncoupled or disrupted mitochondria was not affected by the compounds. We propose, therefore, that RLA acts as a mitochondrial uncoupler of oxidative phosphorylation, a property that arises from the biotransformation (reduction) of LA, and LA acts in other mitochondrial membrane components rather than the ATP synthase affecting the mitochondrial bioenergetics. Such effects may account for the well-documented hepatoxicity of lantana.

Topics: Adenosine Triphosphatases; Adenosine Triphosphate; Animals; Chemical and Drug Induced Liver Injury; Energy Metabolism; In Vitro Techniques; Lantana; Male; Membrane Potentials; Mitochondria, Liver; Oleanolic Acid; Osmotic Fragility; Oxidative Phosphorylation; Oxygen Consumption; Rats; Rats, Wistar; Toxins, Biological; Uncoupling Agents

Oral administration of lantana (Lantana camara var. aculeata) leaf powder to guinea pigs at a dose of 6 g/ kg body weight elicited cholestasis. The animals were euthanized 48 h after dosing. Liver homogenates, bile, gall bladder, blood, urine, contents of gastrointestinal tract (GIT) and faeces were analysed for the principal hepatotoxin in lantana leaves viz. lantadene A (LA), its congeners and biotransformation products, using high performance liquid chromatographic technique. Lantadenes could not be detected in liver, bile, gall bladder, blood and urine samples. LA and lantadene B (LB), their derivatives reduced lantadene A (RLA), reduced lantadene B (RLB) and two unidentified metabolites could be detected in the contents of lower GIT and faeces. In vitro incubation of lantana leaf powder with guinea pig caecal contents under anaerobic conditions elicited biotransformation of LA and LB to RLA and RLB, respectively. On the other hand, incubation of lantana leaf powder with cattle rumen liquor under anaerobic conditions did not elicit biotransformation of lantadenes.

Topics: Anaerobiosis; Animals; Bilirubin; Biotransformation; Cecum; Chemical and Drug Induced Liver Injury; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Guinea Pigs; Oleanolic Acid; Plant Leaves; Plants, Toxic

Lantadene A (LA) administered orally to guinea pigs elicited cholestasis. LA could not be detected in liver, bile, gall bladder, blood and urine. LA and its biotransformation product reduced lantadene A (RLA) could be detected in caecum, large intestine, and faeces. In vitro incubation of LA with liver homogenates under aerobic and anaerobic conditions did not elicit its biotransformation to RLA. On the other hand, in vitro incubation of LA with guinea pig caecal and large intestinal contents under anaerobic conditions elicited conversion of LA to RLA. This is the first report of the biotransformation of LA in the animal system.

Topics: Aerobiosis; Anaerobiosis; Animals; Biotransformation; Cecum; Chemical and Drug Induced Liver Injury; Chromatography, Thin Layer; Female; Guinea Pigs; In Vitro Techniques; Intestine, Large; Liver; Oleanolic Acid; Tissue Distribution; Toxins, Biological; Triterpenes

Liver injury occurred after sheep were injected intravenously with the triperpene acid lantadene A, the toxic principle of the tropical plant Lantana camara. A single dose of 1--3 mg/kg of the compound caused mild hepatocellular injury characterized by transient rises in serum enzymes, with or without hyperbilirubinaemia. Higher doses resulted in hepatic necrosis. When low doses of the triterpene were given repeatedly over several days a cholestatic syndrome developed which appeared identical with that caused by consumption of the plant. This is a disease model which may be of value in experimental studies of intrahepatic cholestasis. This study provides evidence that lantadene A is hepatotoxic and does not require metabolism in the alimentray tract for toxicity in sheep.

Topics: Animals; Chemical and Drug Induced Liver Injury; Cholestasis; Liver Diseases; Necrosis; Oleanolic Acid; Plant Extracts; Sheep; Sheep Diseases; Triterpenes