Inhibition of mitochondrial respiration by flavoskyrin, a toxic metabolite of Penicillium islandicum Sopp.

The effects of flavoskyrin, a toxic bianthraquinoid compound from Penicillium islandicum Sopp., on the DNA repair system in rat and mouse hepatocytes and on the ATP biosynthesis system in rat liver mitochondria were studied to gain insight into the mechanism for its cytotoxicity. Flavoskyrin did not elicit unscheduled DNA synthesis (UDS) in hepatocytes at all, implying non-genotoxicity of this compound. Flavoskyrin was found to uncouple oxidative phosphorylation in mitochondria, significantly decreasing both respiratory control (RC) index and P/O ratio. In addition to its uncoupling effect, flavoskyrin produced a marked depression of state-3 respiration, showing 50% inhibition at about 20 microM. These reactions lead to the inhibition of ATP biosynthesis in mitochondria, which may reflect one of the mechanisms of flavoskyrin cytotoxicity.