title: Is propylene oxide induced cell proliferation in rat nasal respiratory epithelium  mediated by a severe depletion of water-soluble non-protein thiol?
abstract: Propylene oxide (PO) concentrations >or=300 ppm induced cell proliferation and tumors in rat nasal respiratory epithelium (NRE). Cell proliferation was suggested to result from depletion of glutathione (GSH) in NRE. In order to substantiate this hypothesis, cell proliferation - measured by bromodeoxyuridine incorporation into DNA of the epithelium lining middle septum, dorsal medial meatus, and medial and lateral surfaces of the nasoturbinate in transverse nasal sections taken immediately posterior to the upper incisor teeth - and water-soluble non-protein thiol (NPSH) in NRE were determined after exposing male Fischer 344 rats to 50 ppm, 100 ppm, 200 ppm, or 300 ppm PO (6 h/day, 3 days). Both parameters were also investigated after treating rats for 3 days with diethylmaleate (DEM; 2 x 250 mg/kg/day or 500 + 150 mg/kg/day) or buthionine sulfoximine (BSO; 500 mg/kg/day). Exposure to 50 ppm PO and treatment with 2 x2 50 mg/kg/day DEM resulted in NPSH levels approximating 50% and 80% of the level in untreated controls, respectively. Cell proliferation did not increase. After exposures to >or= 100 ppm PO or treatment with BSO or 500 + 150 mg/kg/day DEM, NPSH was depleted to <or=1/3 of the control level and cell proliferation increased 2.0-3.7-fold the control value. In conclusion, profound perturbation of the GSH status may represent a crucial step in PO induced rat nasal tumorigenicity.
authors.affiliation: Institute of Toxicology, Helmholtz Zentrum München, Ingolstädter Landstrasse 1, D-85764 Neuherberg, Germany.
authors.forename: Mohammad D H
authors.initials: MD
authors.lastname: Khan
authors.forename: Dominik
authors.initials: D
authors.lastname: Klein
authors.forename: Ilona
authors.initials: I
authors.lastname: Mossbrugger
authors.forename: Doris
authors.initials: D
authors.lastname: Oesterle
authors.forename: György A
authors.initials: GA
authors.lastname: Csanády
authors.forename: Letitia
authors.initials: L
authors.lastname: Quintanilla-Martinez
authors.forename: Johannes G
authors.initials: JG
authors.lastname: Filser
mesh_terms: D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004852:Epoxy Compounds / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism*; D008297:Male; D008298:Maleates / Q000494:pharmacology; D009297:Nasal Mucosa / Q000187:drug effects* / Q000473:pathology; D009669:Nose Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D012995:Solubility; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D013997:Time Factors; D014867:Water / Q000737:chemistry*
chemical_list: D000393:Air Pollutants; D004852:Epoxy Compounds; D008298:Maleates; D013438:Sulfhydryl Compounds; D014867:Water; D019328:Buthionine Sulfoximine; C014476:diethyl maleate; D005978:Glutathione; C009068:propylene oxide