Metabolic activation of phenacetin in rat nasal mucosa: dose-dependent binding to the glands of Bowman.
The metabolism and binding of the analgetic drug [ring-3H]phenacetin in the nasal mucosa were studied in vitro and in vivo in male Sprague-Dawley rats. As shown by whole-body and light microscopic autoradiography there was an irreversible binding of metabolites to the glands of Bowman in the olfactory mucosa after high but not after low doses of [3H]phenacetin. In the other tissues, the distribution of radioactivity was not changed when the dose was increased. Autoradiography of [3H]-acetaminophen showed no preferential uptake of radioactivity in the olfactory mucosa. At incubation of nasal septa with [3H]phenacetin in vitro, a binding of metabolites to the glands of Bowman was observed indicating that the metabolism occurred in situ. In rats, glutathione (GSH) depleted by pretreatment with phorone, there was a binding to the glands of Bowman in the olfactory mucosa also after a trace dose of [3H]phenacetin. Addition of GSH decreased the irreversible binding of [3H]phenacetin metabolites that occurred in 9000 X g nasal mucosa supernatants incubated with [3H]phenacetin. There was a moderate decrease in the level of nonprotein sulfhydryl groups, mainly GSH, in the olfactory mucosa after administration of 100-300 mg/kg phenacetin. Collectively, these data suggest that phenacetin is metabolized and subsequent to GSH depletion, bound preferentially in the glands of Bowman. The data also suggest that in situ metabolic activation and binding of phenacetin in the rat nasal mucosa at high doses may play a role in the pathogenesis of the nasal tumors induced by high doses of phenacetin in the rat.
D000818:Animals; D001345:Autoradiography; D001711:Biotransformation; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007659:Ketones / Q000494:pharmacology; D008297:Male; D009297:Nasal Mucosa / Q000032:analysis / Q000187:drug effects / Q000378:metabolism*; D010615:Phenacetin / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013438:Sulfhydryl Compounds / Q000032:analysis; D014018:Tissue Distribution; D014316:Tritium
D007659:Ketones; D013438:Sulfhydryl Compounds; D014316:Tritium; C018637:phorone; D010615:Phenacetin