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Invest Ophthalmol Vis Sci. 2017 Apr 1;58(4):2406-2412. doi: 10.1167/iovs.16-20903.

The Eye Drop Preservative Benzalkonium Chloride Potently Induces Mitochondrial Dysfunction and Preferentially Affects LHON Mutant Cells.

Author information

1
Department of Molecular Bioscience, School of Veterinary Medicine, University of California, Davis, Davis, California, United States.
2
Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Institut de la Vision, Paris, France 3CHNO des Quinze-Vingts, DHU Sight Restore, INSERM-DHOS CIC, Paris, France 4Université Versailles-Saint-Quentin-en-Yvelines UVSQ, Hôpital Ambroise Paré, APHP, Boulogne-Billancourt, France.
3
Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Institut de la Vision, Paris, France 3CHNO des Quinze-Vingts, DHU Sight Restore, INSERM-DHOS CIC, Paris, France 5Université Sorbonne Paris Cité USPC, Université Paris Descartes, Faculté de Pharmacie de Paris, Paris, France.
4
Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Institut de la Vision, Paris, France 3CHNO des Quinze-Vingts, DHU Sight Restore, INSERM-DHOS CIC, Paris, France.

Abstract

Purpose:

Benzalkonium chloride (BAK) is the most commonly used eye drop preservative. Benzalkonium chloride has been associated with toxic effects such as "dry eye" and trabecular meshwork degeneration, but the underlying biochemical mechanism of ocular toxicity by BAK is unclear. In this study, we propose a mechanistic basis for BAK's adverse effects.

Method:

Mitochondrial O2 consumption rates of human corneal epithelial primary cells (HCEP), osteosarcoma cybrid cells carrying healthy (control) or Leber hereditary optic neuropathy (LHON) mutant mtDNA [11778(G>A)], were measured before and after acute treatment with BAK. Mitochondrial adenosine triphosphate (ATP) synthesis and cell viability were also measured in the BAK-treated control: LHON mutant and human-derived trabecular meshwork cells (HTM3).

Results:

Benzalkonium chloride inhibited mitochondrial ATP (IC50, 5.3 μM) and O2 consumption (IC50, 10.9 μM) in a concentration-dependent manner, by directly targeting mitochondrial complex I. At its pharmaceutical concentrations (107-667 μM), BAK inhibited mitochondrial function >90%. In addition, BAK elicited concentration-dependent cytotoxicity to cybrid cells (IC50, 22.8 μM) and induced apoptosis in HTM3 cells at similar concentrations. Furthermore, we show that BAK directly inhibits mitochondrial O2 consumption in HCEP cells (IC50, 3.8 μM) at 50-fold lower concentrations than used in eye drops, and that cells bearing mitochondrial blindness (LHON) mutations are further sensitized to BAK's mitotoxic effect.

Conclusions:

Benzalkonium chloride inhibits mitochondria of human corneal epithelial cells and cells bearing LHON mutations at pharmacologically relevant concentrations, and we suggest this is the basis of BAK's ocular toxicity. Prescribing BAK-containing eye drops should be avoided in patients with mitochondrial deficiency, including LHON patients, LHON carriers, and possibly primary open-angle glaucoma patients.

PMID:
28444329
PMCID:
PMC5407244
DOI:
10.1167/iovs.16-20903
[Indexed for MEDLINE]
Free PMC Article

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