Metabolism and macromolecular binding of 1-nitronaphthalene in the mouse.
The metabolism and binding of 1-nitronaphthalene (1-NN) to tissue macromolecules was studied in the mouse using tissue microsomes, lung slices, and isolated lung cells. With microsomes, binding was NADPH-dependent. CO inhibited binding in lung microsomes by more than 90% and in liver microsomes by 60-85%. Nitrogen inhibited binding by 70-80% in lung microsomes and 50-75% in liver microsomes. Incubation of the microsomes in pure O2 did not affect the binding of 1-NN. SKF525A inhibited binding in a dose-dependent manner with approximately 50% inhibition of binding obtained at a molar ratio of 1:4, SKF525A/1-NN. The rate of 1-NN binding by liver microsomes was increased by pretreatment of the mice with phenobarbital (1.2 vs. 0.8 nmol/min/mg protein). beta-Naphthoflavone (BNF) pretreatment increased slightly the rate of 1-NN binding by lung microsomes (1.2 vs 0.9 nmol/min/mg protein), but had no effect on binding by liver microsomes. Studies with isolated lung cells indicated that cell cultures enriched in Clara cells were 6-15-fold more active in metabolism and binding of 1-NN than cultures not containing Clara cells. Autoradiography of lung slices incubated in vitro with [14C]1-NN showed the label to be concentrated in the cells of the bronchiolar epithelium. The results indicate that 1-NN is metabolized in vitro by cytochrome P-450 enzymes via an oxidative pathway to bind to tissue macromolecules. Further, this pathway exists in lung cells, and can lead to binding of the compound without the need for extrapulmonary metabolism.
D000818:Animals; D002250:Carbon Radioisotopes; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D004851:Epoxide Hydrolases / Q000502:physiology; D066298:In Vitro Techniques; D008168:Lung / Q000378:metabolism / Q000473:pathology; D046911:Macromolecular Substances; D008297:Male; D051379:Mice; D008861:Microsomes / Q000378:metabolism; D009281:Naphthalenes / Q000378:metabolism* / Q000633:toxicity; D010100:Oxygen / Q000494:pharmacology
D002250:Carbon Radioisotopes; D046911:Macromolecular Substances; D009281:Naphthalenes; D003577:Cytochrome P-450 Enzyme System; C016614:1-nitronaphthalene; D004851:Epoxide Hydrolases; D010100:Oxygen