title: Okadaic acid is taken-up into the cells mediated by human hepatocytes transporter OATP1B3.
abstract: Okadaic acid is known as a diarrheal shellfish poison. It is thought that there is no specific target organ for okadaic acid after it has been absorbed into the body. However, the details of its pharmacokinetics are still unknown. In this study, we demonstrated that okadaic acid was more toxic to the hepatocyte-specific uptake transporter OATP1B1- or OATP1B3-expressing cells than control vector-transfected cells. In addition, PP2A activity, which is a target molecule of okadaic acid, was more potently inhibited by okadaic acid in OATP1B1- or OATP1B3-expressing cells compared with control vector-transfected cells. The cytotoxicity of okadaic acid in OATP1B1- or OATP1B3-expressing cells was attenuated by known substrates of OATP1B1- and OATP1B3, but not in control vector-transfected cells. Furthermore, after uptake inhibition study using OATP1B3-expressing cells, Dixon plot showed that okadaic acid inhibited the uptake of hepatotoxin microcystin-LR, which is a substrate for OATP1B1 and OATP1B3, in a competitive manner. These results strongly suggested that okadaic acid is a substrate for OATP1B3 and probably for OATP1B1, and could be involved in unknown caused liver failure and liver cancer. Since okadaic acid possesses cytotoxicity and cell proliferative activity by virtue of its known phosphatase inhibition activity.
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 Public Health and Environmental Medicine, The Jikei University School of Medicine, Tokyo 105-8461, Japan; Department of Domestic Science, Kagoshima Women's College, Kagoshima 890-8565, 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: Yuta
authors.initials: Y
authors.lastname: Maeda
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: Shinya
authors.initials: S
authors.lastname: Bohda
authors.affiliation: Division of Food and Chemical Biology, Faculty of Fisheries, Kagoshima University, Kagoshima 890-0056, Japan.
authors.forename: Petros Kingstone
authors.initials: PK
authors.lastname: Chigwechokha
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: 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: 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, 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: D065567:Absorption, Physiological / Q000187:drug effects; D000818:Animals; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity; D001667:Binding, Competitive; D001692:Biological Transport / Q000187:drug effects; D002274:Carcinogens, Environmental / Q000378:metabolism* / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D004285:Dogs; D057809:HEK293 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D027381:Liver-Specific Organic Anion Transporter 1; D061985:Madin Darby Canine Kidney Cells; D008387:Marine Toxins / Q000378:metabolism* / Q000633:toxicity; D052998:Microcystins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity; D019319:Okadaic Acid / Q000378:metabolism* / Q000633:toxicity; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3
chemical_list: D001427:Bacterial Toxins; D002274:Carcinogens, Environmental; D027381:Liver-Specific Organic Anion Transporter 1; D008387:Marine Toxins; D052998:Microcystins; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D011994:Recombinant Proteins; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D019319:Okadaic Acid; C057862:cyanoginosin LR
keywords: Hepatotoxicity; Microcystin-LR; OATP1B1; OATP1B3; Okadaic acid