title: High-affinity nasal extraction of vinyl acetate vapor is carboxylesterase dependent.
abstract: Vinyl acetate induces nasal tumors in rats, but not mice. Species differences in airflow patterns, physiology, and biochemistry complicate extrapolation of nasal dosimetry from rats to humans. Physiologically based pharmacokinetic modeling of vinyl acetate dosimetry in rats suggested the presence of a saturable metabolic removal pathway in rat nasal mucus. We explored the possibility that this pathway is either a cytochrome P-450 2E1 (CYP2E1) or high-affinity carboxylesterase. Nasal extraction of vinyl acetate vapor (150 ppm) was measured in the surgically isolated nasal cavity of anesthetized rats. Vinyl acetate (150 ppm) was extracted with 73% efficiency in controls. Pretreatment of rats with the CYP2E1 inhibitor diallyl sulfide (DAS) had no effect on extraction, despite significantly reducing CYP2E1 activity. Pretreatment with bis(p-nitrophenyl) phosphate (BNPP), a carboxylesterase inhibitor, reduced extraction to approximately 41%. Acetaldehyde production was similarly unaffected by DAS but was reduced to 55% of control by BNPP. Rat nasal mucus carboxylesterase activity had a K(m) value (32 microM) similar, within a factor of 2, to the value predicted by the physiologically based model, although V(max) was significantly lower than the model prediction. Histochemical observations support the inference that the high-affinity carboxylesterase is bound to the luminal plasma membrane of nasal tissue and is not readily released by nasal lavage, providing an explanation for the low V(max) of the lavage enzyme. This high-affinity isoenzyme could be important in the removal of odorants from the sensory cell-rich nasal olfactory epithelium.
authors.affiliation: Haskell Laboratory for Toxicology and Industrial Medicine, E. I. du Pont de Nemours and Company, P. O. Box 80038, Wilmington, DE 19880-0038, USA. matthew.s.bogdanffy@usa.dupont.com
authors.forename: M S
authors.initials: MS
authors.lastname: Bogdanffy
authors.forename: L A
authors.initials: LA
authors.lastname: Manning
authors.forename: R
authors.initials: R
authors.lastname: Sarangapani
mesh_terms: D000465:Algorithms; D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D019570:Inhalation Exposure; D008954:Models, Biological; D017817:Nasal Lavage Fluid / Q000737:chemistry / Q000166:cytology; D009297:Nasal Mucosa / Q000201:enzymology* / Q000378:metabolism* / Q000648:ultrastructure; D009596:Nitrophenols / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D014753:Vinyl Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D004791:Enzyme Inhibitors; D009596:Nitrophenols; D014753:Vinyl Compounds; C002887:bis(4-nitrophenyl)phosphate; D019392:Cytochrome P-450 CYP2E1; D002265:Carboxylic Ester Hydrolases; C011566:vinyl acetate