title: Synthesis of 4-[2-aminoethyl(nitrosamino)]-1-pyridin-3-yl-butan-1-one, a new NNK hapten for the induction of N-nitrosamine-specific antibodies.
abstract: 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is one of the most abundant and potent procarcinogens in tobacco smoke. In order to induce a strong and substained antibody response against NNK, we developed a functionalized derivative that closely mimicked its structural features, in particular, the pyridyloxobutyl moiety, the adjacent ketone, and the N-nitrosamino group. This hapten was conjugated via a C 2 linker to the highly immunogenic diphteria toxoid licensed as a vaccine in humans to induce polyclonal and monoclonal antibodies. Two monoclonal antibodies were obtained with Kd values of 45.8 nM (P9D5) and 37.6 nM (P7H3), respectively, for NNK-C 2. Both the monoclonal (P9D5 and P7H3) and polyclonal antibodies reacted strongly with NNK (IC 50 = 80 microM or 160 microM) and NNAL (IC 50 = 29 microM or 93 microM) and to a lesser extent with some of the metabolites of NNK. Interestingly, the mAbs did not react with the metabolites of the detoxification pathways such as NNK-N-Oxide and NNAL-N-Oxide (IC 50 > 512 microM). Therefore, such antibodies detect NNK and NNAL and may have the potential to modulate their redistribution in vivo, perhaps reducing some detrimental effects of smoking.
authors.affiliation: Institute of Immunology, Laboratoire National de Santé, 20A rue Auguste Lumière, L-1011, Luxembourg, Luxembourg.
authors.forename: Emmanuel J F
authors.initials: EJ
authors.lastname: Prodhomme
authors.forename: Corinne
authors.initials: C
authors.lastname: Ensch
authors.forename: Fabienne B
authors.initials: FB
authors.lastname: Bouche
authors.forename: Thomas
authors.initials: T
authors.lastname: Kaminski
authors.forename: Sabrina
authors.initials: S
authors.lastname: Deroo
authors.forename: Pierre
authors.initials: P
authors.lastname: Seck
authors.forename: Gilbert
authors.initials: G
authors.lastname: Kirsch
authors.forename: Claude P
authors.initials: CP
authors.lastname: Muller
mesh_terms: D000906:Antibodies / Q000097:blood / Q000276:immunology*; D002352:Carrier Proteins / Q000737:chemistry / Q000276:immunology; D006241:Haptens / Q000737:chemistry*; D015394:Molecular Structure; D009602:Nitrosamines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000276:immunology*
chemical_list: C525967:4-(2-aminoethyl(nitrosamino))-1-pyridin-3-yl-butan-1-one; D000906:Antibodies; D002352:Carrier Proteins; D006241:Haptens; D009602:Nitrosamines; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone