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 bu t not in non-inducible DBA2 (D2) mice. Our previous studies showed that hig h doses of APAP administered to B6 mice pretreated with beta-naphthoflavone (BNF), a P450 inducer, produced ocular tissue damage but not in D2 mice si milarly treated. We then proposed that the ocular toxicity of APAP is due t o accumulation of its metabolite, NAPQI. In the present work, we tested thi s hypothesis by injecting NAPQI (50 mu g in 2 mu l propyleneglycol/eye) int racamerally 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 no t produce lens opacification. Injection of the solvent propyleneglycol only did not cause cataract. Thus, when NAPQI was injected, P450 inducibility w as not essential for cataract formation. In addition to vacuole formation i n the lens epithelial cells, alterations were observed in the corneal endot helium and ciliary epithelium. The retinal cell layers remained intact. Ext ensive mitochondrial damage and changes in chromatin structure in the nucle us were evident in the affected lens epithelial cells. The present result d issociates APAP ocular toxicity from its metabolic potentiation by P450 enz ymes and will allow us to investigate the mechanism of cataractogenesis in in vitro lens culture systems.