Mitochondrial Dysfunction Is the Focus of Quaternary Ammonium Surfactant Toxicity to Mammalian Epithelial Cells

Abstract

dSurfactants have long been known to have microbicidal action and have been extensively used as antiseptics and disinfectants for a variety of general hygiene and clinical purposes. Among surfactants, quaternary ammonium compounds (QAC) are known to be the most useful antiseptics and disinfectants. However, our previous toxicological studies showed that QAC are also the most toxic surfactants for mammalian cells. An understanding of the mechanisms that underlie QAC toxicity is a crucial first step in their rational use and in the design and development of more effective and safer molecules. We show that QAC-induced toxicity is mediated primarily through mitochondrial dysfunction in mammalian columnar epithelial cell cultures in vitro. Toxic effects begin at sublethal concentrations and are characterized by mitochondrial fragmentation accompanied by decreased cellular energy charge. At very low concentrations, several QAC act on mitochondrial bioenergetics through a common mechanism of action, primarily by inhibiting mitochondrial respiration initiated at complex I and, to a lesser extent, by slowing down coupled ADP phosphorylation. The result is a reduction of cellular energy charge which, when reduced below 50% of its original value, induces apoptosis. The lethal effects are shown to be primarily a result of this process. At higher doses (closer to the critical micellar concentration), QAC induce the complete breakdown of cellular energy charge and necrotic cell death.T he microbicidal activity of surfactants has generally been attributed to their ability to destroy cell membrane structure (1). This destructive action results from preferred partitioning of surfactants from the aqueous phase into cell membranes where, at low concentrations, they may affect some subtle physical properties (lipid bilayer curvature, lateral pressure, surface charge, etc.) which then affect membrane protein function, without a gross destruction of the membrane. At higher concentrations, closer to the surfactant critical micellar concentration (CMC), an equilibrium is established between the cell membrane components associated with the lipid bilayer phase and a coexisting micellar pseudophase in the aqueous medium that results in a dissolution of several components of the lipid bilayer into micelles, destruction of cell membrane integrity, and cell lysis (2, 3).Our interest in the potential use of surfactants as microbicides in sexually transmitted infections (STI) led us to compare surfactant toxicities to in vitro cultures of mammalian columnar epithelial cells with their ability to kill some bacterial and yeast STI pathogens (4). Interestingly, among all of the surfactant families (nonionic, zwitterionic, anionic, and cationic) examined, cationic surfactants were the only group in which cytotoxicity occurred at concentrations that were too low to provoke cell lysis. Bacterial growth in cultures was also shown to be inhibited at concentrations that were sublethal to epithelial cells. We then systematically evaluated the cytotoxici...

Quaternary ammonium compounds (QACs): A review on occurrence, fate and toxicity in the environment

“…Furthermore, there are studies that indicated the potential genotoxic effects of QACs to exposed eukaryotic cells at concentrations commonly found in wastewaters and employed in commercially available nasal preparations (Deutschle et al, 2006;Ferk et al, 2007). An in vitro study conducted by Inacio and coworkers has shown that QACs cause mitochondrial dysfunction in the mammalian epithelial cell (Inacio et al, 2013). Melin et al (2014) also reported that exposure of mice to QAC disinfectant significantly damaged its reproduction health.…”

Quaternary ammonium-based biomedical materials: State-of-the-art, toxicological aspects and antimicrobial resistance

“…Mitochondria act as sensors and amplifiers in determining the execution of cell death or apoptosis through regulation of cellular energy metabolism (mitochondrial respiration and oxidative phosphorylation) [377]. Mitochondrial dysfunction and perturbation of cellular energetic mechanisms are involved in QAC-induced toxicity [367,[378][379][380]. At very low concentrations, QACs inhibit mitochondrial respiration and oxidative phosphorylation.…”

Highly hydrophilic cationic gold nanorods stabilized by novel quaternary ammonium surfactant with negligible cytotoxicity

“…With regard to a model of cell membranes as a fluid‐like bilayer arrangement of phospholipids, the cytotoxic effect of QAS is generally attributed to their penetration into phospholipids membrane and formation of membrane lipid/protein‐QAS mixed micelles resulting in disruption of cell membrane integrity and membrane ruptures . However, as the cytotoxicity of QAS was observed also at low doses where the cell lysis was not observed , the toxic effects can occur also as a result of membrane potential changes due to blocking of potassium channels , mitochondrial dysfunction or cell cycle arrest .…”