title: Tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone initiates and enhances pancreatitis responses.
abstract: Clinical studies indicate that cigarette smoking increases the risk for developing acute pancreatitis. The nicotine metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a major cigarette smoke toxin. We hypothesized that NNK could sensitize to pancreatitis and examined its effects in isolated rat pancreatic acini and in vivo. In acini, 100 nM NNK caused three- and fivefold activation of trypsinogen and chymotrypsinogen, respectively, above control. Furthermore, NNK pretreatment in acini enhanced zymogen activation in a cerulein pancreatitis model. The long-term effects of NNK were examined in vivo after intraperitoneal injection of NNK (100 mg/kg body wt) three times weekly for 2 wk. NNK alone caused zymogen activation (6-fold for trypsinogen and 2-fold for chymotrypsinogen vs. control), vacuolization, pyknotic nuclei, and edema. This NNK pretreatment followed by treatment with cerulein (40 μg/kg) for 1 h to induce early pancreatitis responses enhanced trypsinogen and chymotrypsinogen activation, as well as other parameters of pancreatitis, compared with cerulein alone. Potential targets of NNK include nicotinic acetylcholine receptors and β-adrenergic receptors; mRNA for both receptor types was detected in acinar cell preparations. Studies with pharmacological inhibitors of these receptors indicate that NNK can mediate acinar cell responses through an nonneuronal α(7)-nicotinic acetylcholine receptor (α(7)-nAChR). These studies suggest that prolonged exposure to this tobacco toxin can cause pancreatitis and sensitize to disease. Therapies targeting NNK-mediated pathways may prove useful in treatment of smoking-related pancreatitis.
authors: Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors: M
authors: M
authors: Alexandre
authors: A K
authors: AK
authors: Uduman
authors: S
authors: S
authors: Minervini
authors: A
authors: A
authors: Raoof
authors: C A
authors: CA
authors: Shugrue
authors: E O
authors: EO
authors: Akinbiyi
authors: V
authors: V
authors: Patel
authors: M
authors: M
authors: Shitia
authors: T R
authors: TR
authors: Kolodecik
authors: R
authors: R
authors: Patton
authors: F S
authors: FS
authors: Gorelick
authors: E C
authors: EC
authors: Thrower
mesh_terms: D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D002478:Cells, Cultured; D002108:Ceruletide / Q000008:administration & dosage / Q000633:toxicity; D004487:Edema / Q000139:chemically induced; D004792:Enzyme Precursors / Q000235:genetics / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D009602:Nitrosamines / Q000008:administration & dosage / Q000633:toxicity*; D010179:Pancreas / Q000187:drug effects*; D010195:Pancreatitis / Q000139:chemically induced*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000235:genetics / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism; D012844:Sincalide / Q000031:analogs & derivatives / Q000494:pharmacology; D064569:alpha7 Nicotinic Acetylcholine Receptor; D014026:Nicotiana
chemical_list: D002273:Carcinogens; C579165:Chrna7 protein, rat; D004792:Enzyme Precursors; D009602:Nitrosamines; D011943:Receptors, Adrenergic, beta; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C058451:JMV 180; D008464:Mecamylamine; D001285:Atropine; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D002108:Ceruletide; D007770:L-Lactate Dehydrogenase; D012844:Sincalide