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Histocytological study on the possible mechanism of acetaminophen cataractogenesis in mouse eye
1Kresge Eye Institute, Department of Ophthalmology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Abstract:
Ocular toxicity of acetaminophen was investigated in cytochrome P450 inducer-responsive and nonresponsive strains of mice by light and electron microscopy. Acetaminophen injected into C57BL6 mice (responsive strain) that had been pretreated with beta-naphthoflavone produced cataract. The drug did not induce cataract in C57BL6 mice without the pretreatment or in DBA2 mice (nonresponsive strain) similarly pretreated with beta-naphthoflavone. Therefore, induction of cytochrome P450 enzymes that metabolically activate acetaminophen is essential for cataractogenesis. Following acetaminophen injection, tissue damage became noticeable first in the ciliary epithelium and then spread to the iris, corneal endothelium, and lens. The neural retina, retinal pigmented epithelium, and choroid remained unaffected. A close examination of tissues revealed that mitochondria are the primary target of acetaminophen cytotoxicity in ocular tissues affected. The nucleus, endoplasmic reticulum, and other subcellular structures appeared normal. The course of propagation of tissue damage and the almost exclusive damage to mitochondria suggest that the cytotoxic metabolite of acetaminophen is secreted with the aqueous humor by the ciliary epithelium and transported to the lens and that inhibition of mitochondrial energy metabolism, together with other effects of the metabolite, contributes to acetaminophen-induced cataract.
Insights
Acetaminophen causes cataracts by damaging ocular mitochondria, but only when cytochrome P450 enzymes are induced. This acetaminophen toxicity requires specific enzyme activation for cataract formation.
Area of Science:
- Ophthalmology
- Toxicology
- Biochemistry
Background:
- Acetaminophen (APAP) is a common analgesic with known hepatotoxicity.
- Ocular toxicity of APAP is less understood, particularly the role of metabolic activation.
Purpose of the Study:
- To investigate the mechanism of acetaminophen-induced ocular toxicity.
- To determine the role of cytochrome P450 enzymes in acetaminophen-induced cataractogenesis.
Main Methods:
- Utilized light and electron microscopy to examine ocular tissues in mice.
- Administered acetaminophen to cytochrome P450 inducer-responsive (C57BL6) and nonresponsive (DBA2) mice, with and without beta-naphthoflavone pretreatment.
- Assessed cataract formation and tissue damage progression.
Main Results:
- Cataracts formed in C57BL6 mice pretreated with beta-naphthoflavone, indicating cytochrome P450 induction is essential.
- Acetaminophen did not induce cataracts in non-pretreated C57BL6 mice or in DBA2 mice.
- Tissue damage initiated in the ciliary epithelium, spreading to the iris, corneal endothelium, and lens, with mitochondria identified as the primary cellular targets.
Conclusions:
- Cytochrome P450-mediated metabolic activation of acetaminophen is critical for inducing ocular toxicity and cataract formation.
- The cytotoxic metabolite appears to be secreted into the aqueous humor, affecting mitochondria and energy metabolism in ocular tissues.
- Mitochondrial dysfunction is a key factor in acetaminophen-induced cataracts.