Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0086543 (cataract)
 29,165 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The polycyclic aromatic hydrocarbon naphthalene is bioactivated by cytochromes P450 to an electrophilic epoxide intermediate, which subsequently is metabolized to naphthoquinones (NQ) and possibly to a free radical intermediate. These reactive intermediates may bind covalently to lenticular tissues, cause oxidant stress and/or lipid peroxidation, thereby initiating cataracts. To evaluate this hypothesis, male C57BL/6 or DBA/2 mice were treated with naphthalene or one of several naphthoquinone and naphthol metabolites, in the presence or absence of modulators of chemical bioactivation and detoxification. In C57BL/6 mice, cataracts were caused by naphthalene (500-2000 mg/kg ip) in a dose-dependent fashion. The incidence of naphthalene-induced cataracts was decreased by pretreatment with the P450 inhibitors SKF 525A and metyrapone, the antioxidants caffeic acid and vitamin E, the glutathione (GSH) precursor N-acetylcysteine, and the free radical spin trapping agent alpha-phenyl-N-t-butylnitrone (p less than 0.05). Naphthalene cataractogenicity was enhanced by pretreatment with the cytochrome P450 inducer phenobarbital and the GSH depletor diethyl maleate (DEM) (p less than 0.05), and was unaffected by pretreatment with the prostaglandin synthetase inhibitors aspirin or naproxen, or the epoxide hydrolase inhibitor trichloropropene oxide. Cataracts were initiated by 1,2-NQ and 1,4-NQ (5-250 mg/kg ip) in a dose-dependent fashion, with a molar potency about 10-fold higher than that for naphthalene. NQ cataractogenicity was enhanced by pretreatment with DEM (p less than 0.05). 1-Naphthol (56 to 562 mg/kg ip) demonstrated a cataractogenic potency intermediary to that for naphthalene and NQ. DBA/2 mice treated with naphthalene (2000 mg/kg ip), 1,4-NQ (65-250 mg/kg ip), 1,2-NQ (30-250 mg/kg ip), or DEM followed by 1,4-NQ (125 mg/kg ip) did not develop cataracts. These results suggest that naphthalene cataractogenesis in C57BL/6 mice requires P450-catalyzed bioactivation to a reactive intermediate, which may be the NQ and/or a free radical derivative, either of which is dependent upon GSH for detoxification.
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PMID:In vivo murine studies on the biochemical mechanism of naphthalene cataractogenesis. 274 33

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.
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PMID:Cytotoxic metabolite of acetaminophen, N-acetyl-p-benzoquinone imine, produces cataract in DBA2 mice. 1060 76

Acetaminophen, an analgesic/antipyretic, is metabolized by hepatic cytochrome P450 to N -acetyl- p -benzoquinone imine (NAPQI), which is transported by blood circulation to the eye and induces anterior cortical cataract in mice. In this study we injected NAPQI into the anterior chamber of mouse eye and investigated time-dependent cellular responses in the lens. After a lag period of about 2 hr following NAPQI injection, lens opacification as determined by measurement of light scattering by the lens became evident and progressively increased thereafter. There was no difference in the profile of opacity development between a P450-inducer responsive mouse strain and a non-responsive strain. During the lag period, a marked increase in free intracellular Ca(2+)in the lens epithelium was observed at 1 hr by confocal fluorescence microscopy with a Ca(2+)probe. Concurrent with the free Ca(2+)increase, there was a 300% rise in the activity of the non-lysosomal neutral protease calpain in the lens at 1 hr after NAPQI injection. Evidence indicated degradation of vimentin in the lens in which calpain activity was enhanced. Co-injection of calpain inhibitors (N-Ac-Leu-Leu-norleucinol and N-Ac-Leu-Leu-methioninal) with NAPQI protected animals completely from cataract development, although a rise in free intracellular Ca(2+)in the lens epithelium was still observed. Lenses from the protected mice did not exhibit enhanced calpain activity. These results suggest the following sequence of events as a possible mechanism of NAPQI-induced cataract. NAPQI introduced in the anterior chamber of the eye enters the lens epithelial cells and disturbs Ca(2+)homeostasis with a resultant rise in free intracellular Ca(2+)which in turn activates calpain in the epithelium. The neutral protease then degrades cellular proteins (e.g. cytoskeletal proteins) and initiates anterior cortical cataract formation.
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PMID:Cataract formation by a semiquinone metabolite of acetaminophen in mice: possible involvement of Ca(2+)and calpain activation. 1109 8