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Toxicon : official journal of the International Society on Toxinology
Apr 15, 2019;162 1-8.

Nonalcoholic fatty liver disease alters microcystin-LR toxicokinetics and acute toxicity.

John D Clarke, Anika Dzierlenga, Tarana Arman, Erica Toth, Hui Li, Katherine D Lynch, Dan-Dan Tian, Michael Goedken, Mary F Paine, Nathan Cherrington
Author Information
  1. John D Clarke: Department of Pharmaceutical Sciences, Washington State University, Spokane, WA, 99202, USA. Electronic address: j.clarke@wsu.edu.
  2. Anika Dzierlenga: Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, 85721, USA.
  3. Tarana Arman: Department of Pharmaceutical Sciences, Washington State University, Spokane, WA, 99202, USA.
  4. Erica Toth: Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, 85721, USA.
  5. Hui Li: Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, 85721, USA.
  6. Katherine D Lynch: Department of Pharmaceutical Sciences, Washington State University, Spokane, WA, 99202, USA.
  7. Dan-Dan Tian: Department of Pharmaceutical Sciences, Washington State University, Spokane, WA, 99202, USA.
  8. Michael Goedken: Rutgers Translational Sciences, Rutgers University, Piscataway, NJ, 08901, USA.
  9. Mary F Paine: Department of Pharmaceutical Sciences, Washington State University, Spokane, WA, 99202, USA.
  10. Nathan Cherrington: Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, 85721, USA.
PMID: 30849452 DOI: 10.1016/j.toxicon.2019.03.002

Abstract

Microcystin-LR (MCLR) is a cyanotoxin produced by blue-green algae that causes liver and kidney toxicities. MCLR toxicity is dependent on cellular uptake through the organic anion transporting polypeptide (OATP) transporters. Nonalcoholic fatty liver disease (NAFLD) progresses through multiple stages, alters expression of hepatic OATPs, and is associated with chronic kidney disease. The purpose of this study was to determine whether NAFLD increases systemic exposure to MCLR and influences acute liver and kidney toxicities. Rats were fed a control diet or two dietary models of NAFLD; methionine and choline deficient (MCD) or high fat/high cholesterol (HFHC). Two studies were performed in these groups: 1) a single dose intravenous toxicokinetic study (20 μg/kg), and 2) a single dose intraperitoneal toxicity study (60 μg/kg). Compared to control rats, plasma MCLR area under the concentration-time curve (AUC) in MCD rats doubled, whereas biliary clearance (Cl) was unchanged; in contrast, plasma AUC in HFHC rats was unchanged, whereas Cl approximately doubled. Less MCLR bound to PP2A was observed in the liver of MCD rats. This shift in exposure decreased the severity of liver pathology only in the MCD rats after a single toxic dose of MCLR (60 μg/kg). In contrast, the single toxic dose of MCLR increased hepatic inflammation, plasma cholesterol, proteinuria, and urinary KIM1 in HFHC rats more than MCLR exposed control rats. In conclusion, rodent models of NAFLD alter MCLR toxicokinetics and acute toxicity and may have implications for liver and kidney pathologies in NAFLD patients.

Keywords

Acute toxicity Microcystin-LR Nonalcoholic steatohepatitis Toxicokinetics

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Grants

  1. K99 ES024455/NIEHS NIH HHS
  2. P30 ES006694/NIEHS NIH HHS
  3. R00 ES024455/NIEHS NIH HHS
  4. T32 ES007091/NIEHS NIH HHS

MeSH Term

Animals
Cell Adhesion Molecules
Cholesterol
Choline
Diet, High-Fat
Hepatobiliary Elimination
Inflammation
Kidney
Liver
Male
Marine Toxins
Methionine
Microcystins
Non-alcoholic Fatty Liver Disease
Organic Anion Transporters
Protein Phosphatase 2
Proteinuria
Rats, Sprague-Dawley
Toxicokinetics

Chemicals

Cell Adhesion Molecules
Havcr1protein, rat
Marine Toxins
Microcystins
Organic Anion Transporters
Cholesterol
Methionine
Protein Phosphatase 2
cyanoginosin LR
Choline
Journal Article
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Word Cloud

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