title: Inhibition of pancreatic acinar mitochondrial thiamin pyrophosphate uptake by the cigarette smoke component 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.
abstract: Thiamin is essential for normal metabolism in pancreatic acinar cells (PAC) and is obtained from their microenvironment through specific plasma-membrane transporters, converted to thiamin pyrophosphate (TPP) in the cytoplasm, followed by uptake of TPP by mitochondria through the mitochondrial TPP (MTPP) transporter (MTPPT; product of SLC25A19 gene). TPP is essential for normal mitochondrial function. We examined the effect of long-term/chronic exposure of PAC in vitro (pancreatic acinar 266-6 cells) and in vivo (wild-type or transgenic mice carrying the SLC25A19 promoter) of the cigarette smoke toxin, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), on the MTPP uptake process. Our in vitro and in vivo findings demonstrate that NNK negatively affects MTPP uptake and reduced expression of MTPPT protein, MTPPT mRNA, and heterogenous nuclear RNA, as well as SLC25A19 promoter activity. The effect of NNK on Slc25a19 transcription was neither mediated by changes in expression of transcriptional factor NFY-1 (known to drive SLC25A19 transcription), nor due to changes in methylation profile of the Slc25a19 promoter. Rather, it appears to be due to changes in histone modifications that involve significant decreases in histone H3K4-trimethylation and H3K9-acetylation (activation markers). The effect of NNK on MTPPT function is mediated through the nonneuronal α7-nicotinic acetylcholine receptor (α7-nAChR), as indicated by both in vitro (using the nAChR antagonist mecamylamine) and in vivo (using an α7-nAchR(-/-) mouse model) studies. These findings demonstrate that chronic exposure of PAC to NNK negatively impacts PAC MTPP uptake. This effect appears to be exerted at the level of Slc25a19 transcription, involve epigenetic mechanism(s), and is mediated through the α7-nAchR.
authors.affiliation: Department of Medical Research, Veterans Affairs Medical Center, Long Beach, California; Departments of Medicine and Physiology/Biophysics, University of California, Irvine, California;
authors.forename: Padmanabhan
authors.initials: P
authors.lastname: Srinivasan
authors.affiliation: Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut;
authors.forename: Edwin C
authors.initials: EC
authors.lastname: Thrower
authors.affiliation: Section of Digestive Diseases, Department of Internal Medicine, Yale University, New Haven, Connecticut; and Veterans Affairs Healthcare System, West Haven, Connecticut.
authors.forename: Fred S
authors.initials: FS
authors.lastname: Gorelick
authors.affiliation: Department of Medical Research, Veterans Affairs Medical Center, Long Beach, California; Departments of Medicine and Physiology/Biophysics, University of California, Irvine, California; hmsaid@uci.edu.
authors.forename: Hamid M
authors.initials: HM
authors.lastname: Said
mesh_terms: D061354:Acinar Cells / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D027321:Anion Transport Proteins / Q000235:genetics / Q000378:metabolism; D001692:Biological Transport; D002273:Carcinogens / Q000633:toxicity*; D002460:Cell Line; D006657:Histones / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009602:Nitrosamines / Q000633:toxicity*; D010179:Pancreas / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013835:Thiamine Pyrophosphate / Q000378:metabolism*; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*
chemical_list: D027321:Anion Transport Proteins; D002273:Carcinogens; D006657:Histones; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; D009602:Nitrosamines; D012333:RNA, Messenger; C515239:Slc25a19 protein, mouse; D014028:Tobacco Smoke Pollution; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D013835:Thiamine Pyrophosphate
keywords: NNK; cigarette smoke; mitochondrial thiamin pyrophosphate transport; pancreatic acinar cells