NAD-dependent isocitrate dehydrogenase as a novel target of tributyltin in human embryonic carcinoma cells

Shigeru Yamada; Yaichiro Kotake; Yosuke Demizu; Masaaki Kurihara; Yuko Sekino; Yasunari Kanda

doi:10.1038/srep05952

NAD-dependent isocitrate dehydrogenase as a novel target of tributyltin in human embryonic carcinoma cells

Sci Rep. 2014 Aug 5:4:5952. doi: 10.1038/srep05952.

Authors

Shigeru Yamada¹, Yaichiro Kotake², Yosuke Demizu³, Masaaki Kurihara³, Yuko Sekino¹, Yasunari Kanda¹

Affiliations

¹ Division of Pharmacology, National Institute of Health Sciences, Tokyo, Japan.
² Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
³ Division of Organic Chemistry, National Institute of Health Sciences, Tokyo, Japan.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Differentiation / drug effects
Cell Line, Tumor
Citric Acid Cycle / drug effects*
Embryo, Mammalian
Endocrine Disruptors / chemistry
Endocrine Disruptors / toxicity*
Environmental Pollutants / chemistry
Environmental Pollutants / toxicity*
Humans
Isocitrate Dehydrogenase / antagonists & inhibitors*
Isocitrate Dehydrogenase / metabolism
Isocitrates / antagonists & inhibitors
Isocitrates / metabolism
Ketoglutaric Acids / antagonists & inhibitors
Ketoglutaric Acids / metabolism
Malates / antagonists & inhibitors
Malates / metabolism
Male
Molecular Docking Simulation
Neurons / drug effects
Neurons / metabolism
Neurons / pathology
Succinic Acid / antagonists & inhibitors
Succinic Acid / metabolism
Testis / drug effects
Testis / metabolism
Testis / pathology
Trialkyltin Compounds / chemistry
Trialkyltin Compounds / toxicity*

Substances

Endocrine Disruptors
Environmental Pollutants
Isocitrates
Ketoglutaric Acids
Malates
Trialkyltin Compounds
tributyltin
malic acid
isocitric acid
Succinic Acid
Isocitrate Dehydrogenase