Acteoside from Conandron ramondioides Reduces Microcystin-LR Cytotoxicity by Inhibiting Intracellular Uptake Mediated by OATP1B3
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- Shota Takumi
- Division of Food and Chemical Biology, Faculty of Fisheries, Kagoshima University, Kagoshima, Japan
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- Kairi Hashimoto
- Division of Food and Chemical Biology, Faculty of Fisheries, Kagoshima University, Kagoshima, Japan
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- Masaru Tomioka
- Division of Food and Chemical Biology, Faculty of Fisheries, Kagoshima University, Kagoshima, Japan
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- Mina Sato
- Division of Food and Chemical Biology, Faculty of Fisheries, Kagoshima University, Kagoshima, Japan
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- Weijie He
- Division of Food and Chemical Biology, Faculty of Fisheries, Kagoshima University, Kagoshima, Japan
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- Yumiko Komatsu
- Department of Domestic Science, Kagoshima Womenʼs College, Kagoshima, Japan
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- Shunji Aoki
- Department of Pharmacy, School of Pharmacy, Hyogo Medical University, Kobe, Japan
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- Ryuji Ikeda
- Department of Pharmacy, University of Miyazaki Hospital, Miyazaki, Japan
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- Kazuhiro Shiozaki
- Division of Food and Chemical Biology, Faculty of Fisheries, Kagoshima University, Kagoshima, Japan
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- Tatsuhiko Furukawa
- Department of Pathology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
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- Masaharu Komatsu
- Division of Food and Chemical Biology, Faculty of Fisheries, Kagoshima University, Kagoshima, Japan
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<jats:title>Abstract</jats:title><jats:p>The hepatotoxin microcystin-LR is a strong inhibitor of serine/threonine protein phosphatase (PP) 1 and PP2A. The onset of its cytotoxicity depends on its selective uptake via the hepatocyte uptake transporters, organic anion transporting polypeptide (OATP) 1B1 and OATP1B3. Understanding and preventing the cytotoxicity of microcystin-LR is crucial to maintain human health. This chemoprevention study demonstrates that the herbal plant extract of iwajisha (20 µg/mL) reduced microcystin-LR cytotoxicity in OATP1B3-expressing cells by approximately six times. In addition, 20 µM acteoside, which is one of the major compounds in iwajisha, reduced microcystin-LR cytotoxicity by approximately 7.4 times. Acteoside could also reduce the cytotoxicity of other compounds, such as okadaic acid and nodularin, which are both substrates of OATP1B3 and inhibitors of PP1/PP2A. To investigate the mechanism by which the cytotoxicity of microcystin-LR is attenuated by acteosides, microcystin-LR and microcystin-LR-binding proteins in cells were examined after microcystin-LR and acteosides were co-exposed. Thus, acteoside noncompetitively inhibited microcystin-LR uptake by OATP1B3-expressing cells. Furthermore, acteoside inhibited the intracellular interaction of microcystin-LR with its binding protein(s), including the 22 kDa protein. Furthermore, using immunoblot analysis, acteoside induced the phosphorylation of extracellular signal-regulated kinase (ERK), which is one of the survival signaling molecules. These results suggest that acteoside reduces microcystin-LR cytotoxicity through several mechanisms, including the inhibition of microcystin-LR uptake via OATP1B3, and decreased interaction between microcystin-LR and its binding protein(s), and that ERK signaling activation contributes to the attenuation effect of acteoside against microcystin-LR cytotoxicity.</jats:p>
収録刊行物
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- Planta Medica
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Planta Medica 89 (06), 616-623, 2023-01-10
Georg Thieme Verlag KG
