title: A relevant dose of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone is extensively metabolized and rapidly absorbed in the canine tracheal mucosa.
abstract: Lung cancer is largely a site-of-entry disease caused by inhaled carcinogenic agents, especially tobacco smoke. Two major groups of procarcinogens, tobacco-specific nitrosamines and polycyclic aromatic hydrocarbons, are putative agents, but their relative contributions are disputed. An important indicator of relative potency for these compounds is the dose to the target epithelial cells. Although we have reported the dose of polycyclic aromatic hydrocarbons to the canine tracheal epithelium [Gerde et al., Carcinogenesis (Lond.), 18: 1825-1832, 1997; Gerde et al., Carcinogenesis (Lond.), in press, 1998], the purpose of the current study was to characterize the absorption and metabolism of low levels of one tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), in the canine trachea. One hundred ng of tritiated NNK were instilled in the distal trachea of the dog. Blood was repeatedly sampled from the azygous vein and both sides of the systemic circulation from 15 s to 30 min after instillation. Tissues were then removed and analyzed for the tritiated NNK and its metabolites. Autoradiography was used to determine the depth distribution of tritium in the tracheal mucosa. Most NNK appeared rapidly in the blood draining the airway mucosa, but there was also a slow clearance phase. During absorption, NNK was distributed within the entire depth of the mucosa to the tracheal cartilage; however, a portion was conspicuously bound to the mucin component of the mucous lining layer. Reversible binding to mucin may be largely responsible for the slow clearance phase. Despite the rapid absorption of most of the tritium, NNK was nonetheless extensively metabolized in the tracheal mucosa. Systemic metabolism was also rapid: within 18 min of instillation, the NNK parent compound had disappeared from the systemic circulation, and 45 min after instillation, no NNK was found in the trachea or any distal tissue. Although the rapid absorption and distribution of NNK and its metabolites ensured widespread and extensive distal binding in all tissues, first-pass metabolism and activation of NNK in the airway mucosa were sufficiently rapid to cause levels of binding at the site of absorption to be approximately 20-fold those of distal tissues. NNK may thus act as a site-of-entry carcinogen. This observation may be important in estimating the contribution of NNK to lung cancer relative to other carcinogens and for explaining increased incidences of oral cancers in users of snuff and chewing tobacco in which NNK is present in high concentrations.
authors.affiliation: Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87185, USA.
authors.forename: P
authors.initials: P
authors.lastname: Gerde
authors.forename: B A
authors.initials: BA
authors.lastname: Muggenburg
authors.forename: T
authors.initials: T
authors.lastname: Stephens
authors.forename: J L
authors.initials: JL
authors.lastname: Lewis
authors.forename: K H
authors.initials: KH
authors.lastname: Pyon
authors.forename: A R
authors.initials: AR
authors.lastname: Dahl
mesh_terms: D000042:Absorption; D000280:Administration, Inhalation; D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity; D004285:Dogs; D004848:Epithelium / Q000378:metabolism; D005260:Female; D008175:Lung Neoplasms / Q000139:chemically induced; D009092:Mucous Membrane / Q000378:metabolism; D009602:Nitrosamines / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity; D014132:Trachea / Q000187:drug effects / Q000378:metabolism*
chemical_list: D002273:Carcinogens; D009602:Nitrosamines; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone