Accepted manuscript
Nonalcoholic fatty liver disease alters microcystin-LR toxicokinetics and acute toxicity
Toxicon (Oxford), Vol.162, pp.1-8
04/15/2019
PMID: 30849452
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 (Clbil) was unchanged; in contrast, plasma AUC in HFHC rats was unchanged, whereas Clbil 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.
•Systemic exposure to MCLR increased approximately two-fold in MCD-induced NAFLD.•Biliary clearance of MCLR increased approximately two-fold in HFHC-induced NAFLD.•MCD-induced NAFLD had the lowest hepatic MCLR levels and hepatic toxicity.•HFHC-induced NAFLD exposed to MCLR had the highest plasma cholesterol, proteinuria, and urinary KIM1.
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Details
- Title
- Nonalcoholic fatty liver disease alters microcystin-LR toxicokinetics and acute toxicity
- Creators
- John D. Clarke - Washington State University, Department of Pharmaceutical SciencesAnika Dzierlenga - Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, 85721, USATarana Arman - Washington State University SpokaneErica Toth - University of ArizonaHui Li - University of ArizonaKatherine D. Lynch - Washington State University SpokaneDan-Dan Tian - Department of Pharmaceutical Sciences, Washington State University, Spokane, WA, 99202, USAMichael Goedken - Rutgers, The State University of New JerseyMary F. Paine - Washington State University, Department of Pharmaceutical SciencesNathan Cherrington - Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, 85721, USA
- Publication Details
- Toxicon (Oxford), Vol.162, pp.1-8
- Academic Unit
- Department of Pharmaceutical Sciences
- Publisher
- Elsevier Ltd
- Number of pages
- 8
- Identifiers
- 99901181236401842
- Language
- English
- Resource Type
- Accepted manuscript