Exposure to a Nonionic Surfactant Induces a Response Akin to Heat-Shock Apoptosis in Intestinal Epithelial Cells: Implications for Excipients Safety

Cavanagh, Robert J.; Smith, Paul A.; Stolnik, Snow

Abstract

© 2019 American Chemical Society. Amphipathic, nonionic, surfactants are widely used in pharmaceutical, food, and agricultural industry to enhance product features; as pharmaceutical excipients, they are also aimed at increasing cell membrane permeability and consequently improving oral drugs absorption. Here, we report on the concentration- and time-dependent succession of events occurring throughout and subsequent exposure of Caco-2 epithelium to a "typical" nonionic surfactant (Kolliphor HS15) to provide a molecular explanation for nonionic surfactant cytotoxicity. The study shows that the conditions of surfactant exposure, which increase plasma membrane fluidity and permeability, produced rapid (within 5 min) redox and mitochondrial effects. Apoptosis was triggered early during exposure (within 10 min) and relied upon an initial mitochondrial membrane hyperpolarization (5-10 min) as a crucial step, leading to its subsequent depolarization and caspase-3/7 activation (60 min). The apoptotic pathway appears to be triggered prior to substantial surfactant-induced membrane damage (observed ≥60 min). We hence propose that the cellular response to the model nonionic surfactant is triggered via surfactant-induced increase in plasma membrane fluidity, a phenomenon akin to the stress response to membrane fluidization induced by heat shock, and consequent apoptosis. Therefore, the fluidization effect that confers surfactants the ability to enhance drug permeability may also be intrinsically linked to the propagation of their cytotoxicity. The reported observations have important implications for the safety of a multitude of nonionic surfactants used in drug delivery formulations and to other permeability enhancing compounds with similar plasma membrane fluidizing mechanisms.

Citation

Cavanagh, R. J., Smith, P. A., & Stolnik, S. (2019). Exposure to a Nonionic Surfactant Induces a Response Akin to Heat-Shock Apoptosis in Intestinal Epithelial Cells: Implications for Excipients Safety. Molecular Pharmaceutics, 16(2), 618-631. https://doi.org/10.1021/acs.molpharmaceut.8b00934

• Journal Article Type: Article
• Acceptance Date: Jan 4, 2019
• Online Publication Date: Jan 4, 2019
• Publication Date: Feb 4, 2019
• Deposit Date: Nov 20, 2019
• Publicly Available Date: Jan 5, 2020
• Journal: Molecular Pharmaceutics
• Print ISSN: 1543-8384
• Electronic ISSN: 1543-8392
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 16
• Issue: 2
• Pages: 618-631
• DOI: https://doi.org/10.1021/acs.molpharmaceut.8b00934
• Public URL: https://nottingham-repository.worktribe.com/output/1864012
• Publisher URL: https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.8b00934
• Additional Information: This document is the unedited Author’s version of a submitted Work that was subsequently accepted for publication in Molecular Pharmaceutics, copyright © American Chemical Society after peer review. To access the final edited and published work see https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.8b00934
• Contract Date: Nov 20, 2019