Histocytological study on the possible mechanism of acetaminophen cataractogenesis in mouse eye.
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.
Zhao
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C
Kresge Eye Institute, Department of Ophthalmology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Shichi
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H
D000082:Acetaminophen / Q000008:administration & dosage / Q000633:toxicity*; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D002386:Cataract / Q000139:chemically induced*; D002924:Ciliary Body / Q000098:blood supply / Q000648:ultrastructure; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D004848:Epithelium / Q000648:ultrastructure; D005123:Eye / Q000473:pathology* / Q000648:ultrastructure; D005128:Eye Diseases / Q000139:chemically induced* / Q000473:pathology; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure; D019108:Tight Junctions / Q000187:drug effects / Q000648:ultrastructure; D019324:beta-Naphthoflavone / Q000008:administration & dosage
D018712:Analgesics, Non-Narcotic; D004791:Enzyme Inhibitors; D000082:Acetaminophen; D019324:beta-Naphthoflavone