Kinetics of nasal carboxylesterase-mediated metabolism of vinyl acetate.
Vinyl acetate vapor has been shown to produce tumors of the nasal cavity in rats, but not mice, exposed by the inhalation route. Carboxylesterase-mediated hydrolysis of vinyl acetate produces acetic acid and vinyl alcohol, which rearranges to form acetaldehyde, another nasal carcinogen that could be the ultimate carcinogenic metabolite of vinyl acetate. The purpose of this study was to define the kinetics of hydrolysis of vinyl acetate in nasal respiratory and olfactory mucosa of male and female rats and mice. The results showed few differences in kinetic parameters between male and female rats or mice. Differences were observed between mucosae. In respiratory mucosa, Vmax ranged from approximately 22-46 mumol/min/mg protein. In olfactory mucosa, Vmax was significantly higher and ranged from 89 to 165 mumol/min/mg protein. Substrate inhibition was apparent at high substrate concentrations in some cases and for those, a kinetic model that accounted for substrate inhibition fit the data better than a Michaelis-Menten model. The substrate inhibition model yielded Vmax values for olfactory tissues that ranged from 113 to 254 mumol/min/mg protein. The second-order rate constant for binding and catalysis, V/K, ranged from 52 to 79 mumol/min/mg/mM for respiratory tissue and from 270 to 469 mumol/min/mg/mM for olfactory tissue. KM derived from the best-fit models was similar for most tissues and ranged from 0.30 to 1.07 mM. These data demonstrate the high capacity of nasal tissue to metabolize vinyl acetate to acetaldehyde and may explain, in part, vinyl acetate-induced nonneoplastic nasal lesion distribution. However, the data do not account for the species difference in susceptibility to the carcinogenic effects of vinyl acetate.
Bogdanffy
M S
MS
Haskell Laboratory for Toxicology and Industrial Medicine, E.I. du Pont de Nemours and Co., Newark, DE 19714.
Taylor
M L
ML
D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000494:pharmacology*; D002273:Carcinogens / Q000378:metabolism; D005260:Female; D006868:Hydrolysis; D007700:Kinetics; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009297:Nasal Mucosa / Q000201:enzymology*; D009831:Olfactory Mucosa / Q000201:enzymology*; D051381:Rats; D011919:Rats, Inbred Strains; D014753:Vinyl Compounds / Q000378:metabolism*
D002273:Carcinogens; D014753:Vinyl Compounds; D002265:Carboxylic Ester Hydrolases; C011566:vinyl acetate