Mechanism of triclosan toxicity: Mitochondrial dysfunction including complex II inhibition, superoxide release and uncoupling of oxidative phosphorylation

• Published in: Toxicology letters 2017-06, Vol.275, p.108-117
• Main Authors: Teplova, Vera V., Belosludtsev, Konstantin N., Kruglov, Alexey G.
• Format: Article
• Language: English
• Subjects: Animals; Anti-Infective Agents, Local - toxicity; Cell Line; Cell Membrane - drug effects; Cell Membrane - metabolism; Cell Membrane - pathology; Complex II inhibitor; Electron Transport Complex II - antagonists & inhibitors; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelial Cells - pathology; Humans; In Vitro Techniques; Male; Membrane Potential, Mitochondrial - drug effects; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria - pathology; Mitochondrial Swelling - drug effects; Oxidative Phosphorylation; Qd-binding site; Rats, Wistar; Superoxide anion; Superoxides - metabolism; Triclosan; Triclosan - toxicity; Uncoupler
• ISSN: 0378-4274; 1879-3169
• DOI: 10.1016/j.toxlet.2017.05.004

[Display omitted] •Triclosan works as protonophore in mitochondrial membranes.•Triclosan stimulates the superoxide release from mitochondria.•Triclosan inhibits complex II in unusual site. Triclosan (5-chloro-2′-(2,4-dichlorophenoxy)phenol), a widely used antibacterial agent, exerts adverse effects on the organism of mammals. Recent research reviled that triclosan at low micromolar concentrations causes mitochondrial dysfunction in many cell types, but the mechanisms of its effect are not fully understood. Here we show that exposure to triclosan disrupted membrane potential, prevented the calcium uptake-driven high-amplitude mitochondrial swelling, stimulated the respiration in the presence of complex I substrates, and suppressed the ADP-stimulated respiration in the presence of complex II substrate, succinate. Triclosan directly inhibited complex II activity. Similar to the complex II inhibitor thenoyltrifluoroacetone, triclosan induced the oxidation of the cytochromes b566 and b562 and caused the release of mitochondrial superoxide. Opposite to thenoyltrifluoroacetone, triclosan increased superoxide release synergistically with myxothiazol but not with antimycin A, indicating different topology of superoxide-producing sites. We concluded that triclosan is unique by its capability of acting as both a protonophore and an unusual complex II inhibitor, which interferes with the mitochondrial respiration by blocking the electron transfer between ubiquinone at the Qd-binding site and heme b. Our data can provide an insight into the mechanisms of the carcinogenic effect of triclosan in the liver and other tissues.