Usnic acid, a lichen
acid, is a compound found in crude medicines and dietary supplements, including
Lipokinetix, a supplement marketed as a
weight loss agent that caused hepatotoxicity and
acute liver failure in patients. In this study, we examined the toxicity of
usnic acid and assessed whether
usnic acid may be contributing to hepatotoxicity caused by
Lipokinetix. In primary cultured murine hepatocytes,
usnic acid treatment (5 microM) resulted in 98%
necrosis within 16 hr (no apoptosis was detected).
Usnic acid treatment was associated with early inhibition and uncoupling of the electron transport chain in mitochondria of cultured hepatocytes. This inhibition of mitochondria by
usnic acid corresponded with a fall in
ATP levels in hepatocytes. In isolated liver mitochondria,
usnic acid was observed to directly inhibit and uncouple oxidative phosphorylation. Oxidative stress appears to be central in
usnic acid-induced hepatotoxicity based on the following findings: (1) pretreatment with
antioxidants (butylated hydroxytoluene+Vitamin E) decreased
usnic acid-induced
necrosis by nearly 70%; (2) depletion of mitochondrial GSH with
diethylmaleate increased susceptibility of hepatocytes to
usnic acid; (3)
usnic acid treatment was associated with increase
free radical generation, measured using the
fluorescent probe, dichlorodihydrofluorescin. The source of
reactive oxygen species after
usnic acid treatment include autoxidation of
usnic acid and increased
hydrogen peroxide generation by mitochondria caused by
usnic acid inhibition of the respiratory chain, with the latter playing a more prominent role. Taken together, our results suggest that
usnic acid is a strong hepatotoxic agent that triggers oxidative stress and disrupts the normal metabolic processes of cells.
Usnic acid therefore may contribute to the hepatotoxic effects of
Lipokinetix and its use in any supplement must come into question.