Comparative effects of lantadene A and its reduced metabolite on mitochondrial bioenergetics
ABSTRACT 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.
SourceAvailable from: Prasad Jamkhande[Show abstract] [Hide abstract]
ABSTRACT: Liver plays a key role in the metabolism and excretion of xenobiotics which makes it highly susceptible to their adverse and toxic effects. Drugs of synthetic origin are found to be major reason of liver toxicity but some herbs also contributes in same fashion. Various herbal medicines with a history of efficacy are effectively used by humans. However, owing to the presence of different phytoconstituents, which are found to be hepatotoxic, it is needed to focus on such phytochemicals. This review emphasizes some crucial aspects of phytoconstituents that produces hepatotoxicity and possible mechanism responsible for it.
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ABSTRACT: Monensin A is a commercially important natural product isolated from Streptomyces cinnamonensins that is primarily employed to treat coccidiosis. Monensin A selectively complexes and transports sodium cations across lipid membranes and displays a variety of biological properties. In this study, we evaluated the Jacobsen catalyst as a cytochrome P450 biomimetic model to investigate the oxidation of monensin A. Mass spectrometry analysis of the products from these model systems revealed the formation of two products: 3-O-demethyl monensin A and 12-hydroxy monensin A, which are the same ones found in in vivo models. Monensin A and products obtained in biomimetic model were tested in a mitochondrial toxicity model assessment and an antimicrobial bioassay against Staphylococcus aureus, S. aureus methicillin-resistant, Staphylococcus epidermidis, Pseudomonas aeruginosa, and Escherichia coli. Our results demonstrated the toxicological effects of monensin A in isolated rat liver mitochondria but not its products, showing that the metabolism of monensin A is a detoxification metabolism. In addition, the antimicrobial bioassay showed that monensin A and its products possessed activity against Gram-positive microorganisms but not for Gram-negative microorganisms. The results revealed the potential of application of this biomimetic chemical model in the synthesis of drug metabolites, providing metabolites for biological tests and other purposes.BioMed Research International 01/2014; 2014:152102. DOI:10.1155/2014/152102 · 2.71 Impact Factor
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ABSTRACT: 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 C in G. biloba extract. The concentration of ginkgolide B in the sample was found as 0.29%. The elevated levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) 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.Toxicon 01/2014; DOI:10.1016/j.toxicon.2014.01.013 · 2.58 Impact Factor