Cytotoxic metabolite of acetaminophen, N-acetyl-p-benzoquinone imine, produces cataract in DBA2 mice.
Acetaminophen, or N-acetyl-p-aminophenol (APAP), is metabolized to N-acetyl-p-benzoquinone imine (NAPQI) by cytochrome P450 enzymes in the liver. The biotransformation of APAP is enhanced in P450-inducible C57BL6 (B6) mice but not in non-inducible DBA2 (D2) mice. Our previous studies showed that high doses of APAP administered to B6 mice pretreated with beta-naphthoflavone (BNF), a P450 inducer, produced ocular tissue damage but not in D2 mice similarly treated. We then proposed that the ocular toxicity of APAP is due to accumulation of its metabolite, NAPQI. In the present work, we tested this hypothesis by injecting NAPQI (50 microg in 2 microl propyleneglycol/eye) intracamerally into B6 and D2 mice. NAPQI produced cataract within a few hours (mean = 4 hr) both in B6 and D2 mice. Lower concentrations of NAPQI did not produce lens opacification. Injection of the solvent propyleneglycol only did not cause cataract. Thus, when NAPQI was injected, P450 inducibility was not essential for cataract formation. In addition to vacuole formation in the lens epithelial cells, alterations were observed in the corneal endothelium and ciliary epithelium. The retinal cell layers remained intact. Extensive mitochondrial damage and changes in chromatin structure in the nucleus were evident in the affected lens epithelial cells. The present result dissociates APAP ocular toxicity from its metabolic potentiation by P450 enzymes and will allow us to investigate the mechanism of cataractogenesis in in vitro lens culture systems.
Qian
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Department of Ophthalmology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
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Shichi
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D000082:Acetaminophen / Q000378:metabolism; D000287:Administration, Topical; D000818:Animals; D016227:Benzoquinones / Q000633:toxicity*; D002386:Cataract / Q000139:chemically induced* / Q000473:pathology; D002843:Chromatin / Q000187:drug effects*; D002923:Cilia / Q000187:drug effects / Q000473:pathology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004727:Endothelium / Q000187:drug effects / Q000473:pathology; D004848:Epithelium / Q000187:drug effects / Q000473:pathology; D007097:Imines / Q000633:toxicity*; D007905:Lens Diseases / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008854:Microscopy, Electron; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D019946:Propylene Glycol / Q000633:toxicity*; D013997:Time Factors
D016227:Benzoquinones; D002843:Chromatin; D007097:Imines; D000082:Acetaminophen; D019946:Propylene Glycol; D003577:Cytochrome P-450 Enzyme System; C028473:N-acetyl-4-benzoquinoneimine