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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.
AuthorsShota Takumi, Satoshi Ikema, Tamami Hanyu, Yusuke Shima, Takashi Kurimoto, Kazuhiro Shiozaki, Yasumasa Sugiyama, Ho-Dong Park, Seiichi Ando, Tatsuhiko Furukawa, Masaharu Komatsu
JournalEnvironmental toxicology and pharmacology (Environ Toxicol Pharmacol) Vol. 39 Issue 2 Pg. 974-81 (Mar 2015) ISSN: 1872-7077 [Electronic] Netherlands
PMID25818985 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2015 Elsevier B.V. All rights reserved.
Chemical References
  • Flavanones
  • Liver-Specific Organic Anion Transporter 1
  • Marine Toxins
  • Microcystins
  • Organic Anion Transporters
  • Organic Anion Transporters, Sodium-Independent
  • Reactive Oxygen Species
  • SLCO1B1 protein, human
  • SLCO1B3 protein, human
  • Solute Carrier Organic Anion Transporter Family Member 1B3
  • Tumor Suppressor Protein p53
  • Hydrogen Peroxide
  • cyanoginosin LR
  • naringin
Topics
  • Cell Survival (drug effects)
  • Flavanones (pharmacology)
  • HEK293 Cells
  • Humans
  • Hydrogen Peroxide (toxicity)
  • Liver-Specific Organic Anion Transporter 1
  • Marine Toxins
  • Microcystins (toxicity)
  • Organic Anion Transporters (metabolism)
  • Organic Anion Transporters, Sodium-Independent (metabolism)
  • Reactive Oxygen Species (metabolism)
  • Solute Carrier Organic Anion Transporter Family Member 1B3
  • Tumor Suppressor Protein p53 (metabolism)

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