title: Naringin attenuates the cytotoxicity of hepatotoxin microcystin-LR by the curious mechanisms to OATP1B1- and OATP1B3-expressing cells.
abstract: Microcystin-LR, which is an inhibitor of serine/threonine protein phosphatase (PP)1 and PP2A, induces liver injury by its selective uptake system into the hepatocyte. It is also thought that microcystin-LR induces reactive oxygen species (ROS). We tried to establish the chemical prevention of microcystin-LR poisoning. We investigated the effect of grapefruit flavanone glycoside naringin on cytotoxicity of microcystin-LR using human hepatocyte uptake transporter OATP1B3-expressing HEK293-OATP1B3 cells. We found cytotoxicity of microcystin-LR was attenuated by naringin in a dose dependent manner. The inhibition magnitude of total cellular serine/threonine protein phosphatase activity induced by microcystin-LR was suppressed by naringin. In addition, uptake of microcystin-LR into HEK293-OATP1B3 cells was inhibited by naringin. Furthermore, microcystin-LR induced phosphorylation of p53 was inhibited by naringin. Regardless of the difference in the exposure pattern of pre-processing and post-processing of naringin, the toxicity of microcystin-LR was comparable. These results suggested that naringin is promising remedy as well as preventive medicine for liver damage with microcystin-LR. In addition, involvement of ROS production after exposure to the sublethal concentrations of microcystin-LR in the onset of cytotoxicity was negligible. Therefore, inhibition of microcystin-LR uptake and the pathway other than ROS production would be involved in the effect of naringin on the attenuation of microcystin-LR toxicity.
authors.affiliation: Department of Public Health and Environmental Medicine, The Jikei University School of Medicine, Tokyo 105-8461, Japan.
authors.forename: Shota
authors.initials: S
authors.lastname: Takumi
authors.affiliation: Division of Food and Chemical Biology, Faculty of Fisheries, Kagoshima University, Kagoshima 890-0056, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ikema
authors.affiliation: Division of Food and Chemical Biology, Faculty of Fisheries, Kagoshima University, Kagoshima 890-0056, Japan; Department of Environmental Sciences, Faculty of Science, Shinshu University, Matsumoto 390-8621, Japan.
authors.forename: Tamami
authors.initials: T
authors.lastname: Hanyu
authors.affiliation: Division of Food and Chemical Biology, Faculty of Fisheries, Kagoshima University, Kagoshima 890-0056, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Shima
authors.affiliation: Division of Food and Chemical Biology, Faculty of Fisheries, Kagoshima University, Kagoshima 890-0056, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kurimoto
authors.affiliation: Division of Food and Chemical Biology, Faculty of Fisheries, Kagoshima University, Kagoshima 890-0056, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Shiozaki
authors.affiliation: Division of Food and Chemical Biology, Faculty of Fisheries, Kagoshima University, Kagoshima 890-0056, Japan.
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Sugiyama
authors.affiliation: Department of Environmental Sciences, Faculty of Science, Shinshu University, Matsumoto 390-8621, Japan.
authors.forename: Ho-Dong
authors.initials: HD
authors.lastname: Park
authors.affiliation: Department of Nutritional Sciences, Faculty of Health and Welfare Science, Nayoro City University, Nayoro, Hokkaido 096-8641, Japan.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Ando
authors.affiliation: Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan; Center for the Research of Advanced Diagnosis and Therapy of Cancer, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Furukawa
authors.affiliation: Division of Food and Chemical Biology, Faculty of Fisheries, Kagoshima University, Kagoshima 890-0056, Japan. Electronic address: komatsu@fish.kagoshima-u.ac.jp.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Komatsu
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D044950:Flavanones / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D027381:Liver-Specific Organic Anion Transporter 1; D008387:Marine Toxins; D052998:Microcystins / Q000633:toxicity*; D027361:Organic Anion Transporters / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D044950:Flavanones; D027381:Liver-Specific Organic Anion Transporter 1; D008387:Marine Toxins; D052998:Microcystins; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D017382:Reactive Oxygen Species; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D016159:Tumor Suppressor Protein p53; D006861:Hydrogen Peroxide; C057862:cyanoginosin LR; C005274:naringin
keywords: Detoxification; Microcystin-LR; Naringin; OATP1B1; OATP1B3