Comparative effects of lantadene A and its reduced metabolite on mitochondrial bioenergetics.
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.
Laboratório de Bioquímica, Faculdade de Zootecnia, UNESP-Univ Estadual Paulista, Campus Experimental de Dracena, Dracena, SP 17900-000, Brazil.
Andréa F
AF
Garcia
Hyllana C D
HC
Medeiros
Marcos A
MA
Maioli
Michele C
MC
Lima
Bruno A
BA
Rocha
Fernando B
FB
da Costa
Carlos
C
Curti
Milton
M
Groppo
Fábio E
FE
Mingatto
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology; D004734:Energy Metabolism / Q000187:drug effects*; D066298:In Vitro Techniques; D032410:Lantana / Q000737:chemistry / Q000633:toxicity*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity; D009996:Osmotic Fragility / Q000187:drug effects; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D014118:Toxins, Biological / Q000737:chemistry / Q000633:toxicity*; D014475:Uncoupling Agents / Q000737:chemistry / Q000633:toxicity
D014118:Toxins, Biological; D014475:Uncoupling Agents; D009828:Oleanolic Acid; D000255:Adenosine Triphosphate; C019074:rehmannic acid; D000251:Adenosine Triphosphatases