Antimicrobial agent triclosan is a proton ionophore uncoupler of mitochondria in living rat and human mast cells and in primary human keratinocytes.
Triclosan (TCS) is an antimicrobial used widely in hospitals and personal care products, at ~10 mm. Human skin efficiently absorbs TCS. Mast cells are ubiquitous key players both in physiological processes and in disease, including asthma, cancer and autism. We previously showed that non-cytotoxic levels of TCS inhibit degranulation, the release of histamine and other mediators, from rat basophilic leukemia mast cells (RBL-2H3), and in this study, we replicate this finding in human mast cells (HMC-1.2). Our investigation into the molecular mechanisms underlying this effect led to the discovery that TCS disrupts adenosine triphosphate (ATP) production in RBL-2H3 cells in glucose-free, galactose-containing media (95% confidence interval EC50 = 7.5-9.7 µm), without causing cytotoxicity. Using these same glucose-free conditions, 15 µm TCS dampens RBL-2H3 degranulation by 40%. The same ATP disruption was found with human HMC-1.2 cells (EC50 4.2-13.7 µm), NIH-3 T3 mouse fibroblasts (EC50 4.8-7.4 µm) and primary human keratinocytes (EC50 3.0-4.1 µm) all with no cytotoxicity. TCS increases oxygen consumption rate in RBL-2H3 cells. Known mitochondrial uncouplers (e.g., carbonyl cyanide 3-chlorophenylhydrazone) previously were found to inhibit mast cell function. TCS-methyl, which has a methyl group in place of the TCS ionizable proton, affects neither degranulation nor ATP production at non-cytotoxic doses. Thus, the effects of TCS on mast cell function are due to its proton ionophore structure. In addition, 5 µm TCS inhibits thapsigargin-stimulated degranulation of RBL-2H3 cells: further evidence that TCS disrupts mast cell signaling. Our data indicate that TCS is a mitochondrial uncoupler, and TCS may affect numerous cell types and functions via this mechanism. Copyright © 2015 John Wiley & Sons, Ltd.
['Weatherly|Lisa M|LM|', 'Shim|Juyoung|J|', 'Hashmi|Hina N|HN|', 'Kennedy|Rachel H|RH|', 'Hess|Samuel T|ST|', 'Gosse|Julie A|JA|']
D000818:Animals D000891:Anti-Infective Agents, Local D016588:Anticarcinogenic Agents D002273:Carcinogens D015550:Cell Degranulation D002460:Cell Line D045744:Cell Line, Tumor D002470:Cell Survival D002478:Cells, Cultured D006801:Humans D015603:Keratinocytes D007700:Kinetics D008407:Mast Cells D051379:Mice D008928:Mitochondria D041681:NIH 3T3 Cells D010085:Oxidative Phosphorylation D051381:Rats D019284:Thapsigargin D014260:Triclosan D014475:Uncoupling Agents
triclosan mast cell RBL-2H3 HMC-1.2 mitochondrial uncoupler triclosan-methyl