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The Eye Drop Preservative Benzalkonium Chloride Potently Induces Mitochondrial Dysfunction and Preferentially Affects LHON Mutant Cells
- Source :
- Investigative Ophthalmology & Visual Science, Investigative ophthalmology & visual science, vol 58, iss 4
- Publication Year :
- 2017
- Publisher :
- The Association for Research in Vision and Ophthalmology, 2017.
-
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.
- Subjects :
- 0301 basic medicine
genetic structures
Mitochondrion
Neurodegenerative
Eye
Ophthalmology & Optometry
Medical and Health Sciences
Benzalkonium chloride
0302 clinical medicine
Adenosine Triphosphate
preservative
Cytotoxicity
Leber
Chemistry
Anatomy
Biological Sciences
3. Good health
Mitochondria
medicine.anatomical_structure
Hereditary
5.1 Pharmaceuticals
Development of treatments and therapeutic interventions
biological phenomena, cell phenomena, and immunity
Benzalkonium Compounds
mitochondrial complex I
medicine.drug
Mitochondrial DNA
Physiology and Pharmacology
Cell Survival
Optic Atrophy, Hereditary, Leber
benzalkonium chloride
Cell Line
03 medical and health sciences
LHON
Oxygen Consumption
Clinical Research
medicine
Humans
Viability assay
Eye Disease and Disorders of Vision
Preservatives, Pharmaceutical
Epithelial Cells
Molecular biology
eye diseases
Optic Atrophy
030104 developmental biology
glaucoma
Apoptosis
Cell culture
Pharmaceutical
030221 ophthalmology & optometry
Trabecular meshwork
sense organs
Ophthalmic Solutions
Preservatives
Subjects
Details
- Language :
- English
- ISSN :
- 15525783 and 01460404
- Volume :
- 58
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Investigative Ophthalmology & Visual Science
- Accession number :
- edsair.doi.dedup.....b7ca3150feb9c854c8a73826542f552e