title: Decrease in acrolein toxicity based on the decline of polyamine oxidases.
abstract: We have shown recently that acrolein is strongly involved in cell damage during brain infarction and chronic renal failure. To study the mechanism of acrolein detoxification, we tried to isolate Neuro2a cells with reduced sensitivity to acrolein toxicity (Neuro2a-ATD cells). In one cell line, Neuro2a-ATD1, the level of glutathione (GSH) was increased. We recently isolated a second cell line, Neuro2a-ATD2, and found that acrolein-producing enzymes [polyamine oxidases (PAO); i.e. acetylpolyamine oxidase (AcPAO), and spermine oxidase (SMO)] are reduced in this cell line due to changes at the level of transcription. In the Neuro2a-ATD2 cells, the IC50of acrolein increased from 4.2 to 6.8μM, and the levels of FosB and C/EBPβ - transcription factors involved in the transcription of AcPAO and SMO genes - were reduced. Transfection of siRNAs for FosB and C/EBPβ reduced the levels of AcPAO and SMO, respectively. In addition, the synthesis of FosB and AcPAO was also decreased by siRNA for C/EBPβ, because C/EBPβ is one of the transcription factors for the FosB gene. It was also found that transfection of siRNA for C/EBPβ decreased SMO promoter activity in Neuro2a cells but not in ATD2 cells confirming that a decrease in C/EBPβ is involved in the reduced SMO activity in Neuro2a-ATD2 cells. Furthermore, transfection of the cDNA for AcPAO or SMO into Neuro2a cells increased the toxicity of acrolein. These results suggest that acrolein is mainly produced from polyamines by PAO.
authors: Amine Pharma Research Institute, Innovation Plaza at Chiba University, 1-8-15 Inohana, Chuo-ku, Chiba, 260-0856, Japan.
authors: Takeshi
authors: T
authors: Uemura
authors: Amine Pharma Research Institute, Innovation Plaza at Chiba University, 1-8-15 Inohana, Chuo-ku, Chiba, 260-0856, Japan.
authors: Mizuho
authors: M
authors: Nakamura
authors: Faculty of Pharmacy, Chiba Institute of Science, 15-8 Shiomi-cho, Choshi, Chiba 288-0025, Japan.
authors: Akihiko
authors: A
authors: Sakamoto
authors: RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors: Takehiro
authors: T
authors: Suzuki
authors: RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors: Naoshi
authors: N
authors: Dohmae
authors: Faculty of Pharmacy, Chiba Institute of Science, 15-8 Shiomi-cho, Choshi, Chiba 288-0025, Japan.
authors: Yusuke
authors: Y
authors: Terui
authors: Faculty of Pharmacy, Chiba Institute of Science, 15-8 Shiomi-cho, Choshi, Chiba 288-0025, Japan.
authors: Hideyuki
authors: H
authors: Tomitori
authors: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Bunting Blaustein Building, 1650 Orlearns Street, Baltimore, MD, 21231, USA.
authors: Robert A
authors: RA
authors: Casero
authors: Faculty of Pharmacy, Chiba Institute of Science, 15-8 Shiomi-cho, Choshi, Chiba 288-0025, Japan.
authors: Keiko
authors: K
authors: Kashiwagi
authors: Amine Pharma Research Institute, Innovation Plaza at Chiba University, 1-8-15 Inohana, Chuo-ku, Chiba, 260-0856, Japan; Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8675, Japan. Electronic address: iga16077@faculty.chiba-u.jp.
authors: Kazuei
authors: K
authors: Igarashi
mesh_terms: D000171:Acrolein / Q000633:toxicity*; D000818:Animals; D045744:Cell Line, Tumor; D018076:DNA, Complementary / Q000235:genetics; D051379:Mice; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics / Q000378:metabolism*; D000097667:Polyamine Oxidase
chemical_list: D000171:Acrolein; D018076:DNA, Complementary; D000587:Oxidoreductases Acting on CH-NH Group Donors; D000097667:Polyamine Oxidase
keywords: AP-1 (FosB and JunB) transcription factors; Acrolein toxicity-decreasing cells; C/EBPβ transcription factor; Glutathione; Polyamine oxidases; Polyamines