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Cellular events preceding acetaminophen cataractogenesis studied by confocal fluorescence microscopy
Priya Mathur1, Igor V Peshenko, Hitoshi Shichi
1Department ofOphthalmology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Summary
Acetaminophen (APAP) causes cellular changes in the eye lens, similar to its metabolite NAPQI. These changes, including calpain activation, precede cataract formation and can be prevented by calpain inhibitors.
Area of Science:
- Ophthalmology
- Toxicology
- Cell Biology
Background:
- Acetaminophen (APAP) metabolism by cytochrome P450 (CYP) enzymes generates N-acetyl-p-benzoquinone imine (NAPQI).
- Previous studies showed NAPQI induces mitochondrial dysfunction, calcium (Ca2+) imbalance, and calpain activation in mouse lens epithelium.
Purpose of the Study:
- To investigate if systemic APAP administration triggers similar cellular responses in the lens epithelium before cataract development.
- To characterize lens calpain activity and assess the efficacy of calpain inhibitors in preventing APAP-induced cataracts.
Main Methods:
- Mice received intraperitoneal injections of APAP.
- In situ fluorescence confocal microscopy was used to assess reactive oxygen species, intracellular Ca2+, and calpain activation in the lens epithelium.
- Lens calpain activity was characterized by its Ca2+ dependency.
Main Results:
- APAP injection induced reactive oxygen species, increased intracellular Ca2+, and activated calpain in the lens epithelium.
- These cellular events mirrored those observed with direct NAPQI administration.
- Calpain inhibitors demonstrated a protective effect against cataract development.
Conclusions:
- Systemic APAP exposure elicits early cellular changes in the lens epithelium that are identical to those caused by its toxic metabolite NAPQI.
- Calpain activation is a key event in APAP-induced cataractogenesis.
- Targeting calpain activity presents a potential therapeutic strategy for preventing acetaminophen-induced eye toxicity.