title: NAD-dependent isocitrate dehydrogenase as a novel target of tributyltin in human embryonic carcinoma cells.
abstract: Tributyltin (TBT) is known to cause developmental defects as endocrine disruptive chemicals (EDCs). At nanomoler concentrations, TBT actions were mediated by genomic pathways via PPAR/RXR. However, non-genomic target of TBT has not been elucidated. To investigate non-genomic TBT targets, we performed comprehensive metabolomic analyses using human embryonic carcinoma NT2/D1 cells. We found that 100 nM TBT reduced the amounts of α-ketoglutarate, succinate and malate. We further found that TBT decreased the activity of NAD-dependent isocitrate dehydrogenase (NAD-IDH), which catalyzes the conversion of isocitrate to α-ketoglutarate in the TCA cycle. In addition, TBT inhibited cell growth and enhanced neuronal differentiation through NAD-IDH inhibition. Furthermore, studies using bacterially expressed human NAD-IDH and in silico simulations suggest that TBT inhibits NAD-IDH due to a possible interaction. These results suggest that NAD-IDH is a novel non-genomic target of TBT at nanomolar levels. Thus, a metabolomic approach may provide new insights into the mechanism of EDC action.
authors.affiliation: Division of Pharmacology, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Yamada
authors.affiliation: Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Yaichiro
authors.initials: Y
authors.lastname: Kotake
authors.affiliation: Division of Organic Chemistry, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Demizu
authors.affiliation: Division of Organic Chemistry, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Kurihara
authors.affiliation: Division of Pharmacology, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Sekino
authors.affiliation: Division of Pharmacology, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Yasunari
authors.initials: Y
authors.lastname: Kanda
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002952:Citric Acid Cycle / Q000187:drug effects*; D004622:Embryo, Mammalian; D052244:Endocrine Disruptors / Q000737:chemistry / Q000633:toxicity*; D004785:Environmental Pollutants / Q000737:chemistry / Q000633:toxicity*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007523:Isocitrates / Q000037:antagonists & inhibitors / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000037:antagonists & inhibitors / Q000378:metabolism; D008293:Malates / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D062105:Molecular Docking Simulation; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019802:Succinic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism; D013737:Testis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014220:Trialkyltin Compounds / Q000737:chemistry / Q000633:toxicity*
chemical_list: D052244:Endocrine Disruptors; D004785:Environmental Pollutants; D007523:Isocitrates; D007656:Ketoglutaric Acids; D008293:Malates; D014220:Trialkyltin Compounds; C011559:tributyltin; C030298:malic acid; C034219:isocitric acid; D019802:Succinic Acid; D007521:Isocitrate Dehydrogenase
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