Harmful effects of usnic acid on hepatic metabolism

Usnic acid is a naturally occurring dibenzofuran derivative found in several lichen species. The compound has been marketed as an ingredient of food supplements for weight reduction. There is evidence that the compound acts as an uncoupler of mitochondrial oxidative phosphorylation and it is also clear that consumption of the drug can lead to severe hepatotoxicity depending on the doses. Based on these and other ideas the objective of the present work was to investigate the possible effects of usnic acid on liver metabolism. Livers of male Wistar rats were perfused in a non-recirculating system. Usnic acid stimulated oxygen consumption at low concentrations, diminished the cellular ATP levels, increased the cytosolic but diminished the mitochondrial NADH/NAD(+) ratio, strongly inhibited gluconeogenesis from three different substrates (IC(50) between 1.33 and 3.61 μM), stimulated glycolysis, fructolysis, glycogenolysis and ammoniagenesis and inhibited ureogenesis. The (14)CO(2) production from [1-(14)C]octanoate and [1-(14)C]oleate was increased by usnic acid, but ketogenesis from octanoate was diminished and that from oleate was not affected. It may be concluded that the effects of usnic acid up to 2.5 μM reflect predominantly its activity as an uncoupler. At higher concentrations, however, several other effects may become significant, including inhibition of mitochondrial electron flow and inhibition of medium-chain fatty acid oxidation. In metabolic terms, toxicity of usnic acid can be predicted to be especially dangerous in the fasted state due to the combination of several deleterius events such as diminished hepatic glucose and ketone bodies output to the brain and increased ammonia production.