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Attenuated Ochratoxin A Transporter Expression in a Mouse Model of Nonalcoholic Steatohepatitis Protects against Proximal Convoluted Tubule Toxicity.

Joseph L. Jilek, Kayla L. FROST, Solène MARIE, Cassandra M. MYERS, Michael GOEDKEN, Stephen H. Wright and Nathan J. CHERRINGTON
Drug Metabolism and Disposition December 17, 2021, DMD-MR-2021-000451; DOI: https://doi.org/10.1124/dmd.121.000451
Joseph L. Jilek
1Pharmacology & Toxicology, University of Arizona, United States
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Kayla L. FROST
2Pharmacology and Toxicology, University of Arizona, United States
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Solène MARIE
2Pharmacology and Toxicology, University of Arizona, United States
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Cassandra M. MYERS
2Pharmacology and Toxicology, University of Arizona, United States
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Michael GOEDKEN
3Rutgers Translational Sciences, Rutgers University, United States
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Stephen H. Wright
4Physiology, University of Arizona, United States
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Nathan J. CHERRINGTON
2Pharmacology and Toxicology, University of Arizona, United States
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  • For correspondence: cherrington@pharmacy.arizona.edu
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Abstract

Ochratoxin A (OTA) is an abundant mycotoxin, yet the toxicological impact of its disposition is not well studied. OTA is an organic anion transporter (OAT) substrate primarily excreted in urine despite a long half-life and extensive protein binding. Altered renal transporter expression during disease, including nonalcoholic steatohepatitis (NASH), may influence response to OTA exposure, but the impact of NASH on OTA toxicokinetics, tissue distribution, and associated nephrotoxicity are unknown. By inducing NASH in fast food-dieted/thioacetamide-exposed mice, we evaluated the effect of NASH on a bolus OTA exposure (12.5 mg/kg p.o.) after 3 days. NASH mice presented with less gross toxicity (44% less bodyweight loss) and kidney and liver weights of NASH mice were 11% and 24%, respectively, higher than healthy mice. Organ and body weight changes coincided with reduced renal proximal tubule cells vacuolation, degeneration and necrosis though no OTA-induced hepatic lesions were found. OTA systemic exposure in NASH mice increased modestly from 5.65 {plus minus} 1.10 to 7.95 {plus minus} 0.61 mg*h/mL/kg BW, renal excretion increased robustly from 5.55 {plus minus} 0.37% to 13.11 {plus minus} 3.10%, relative to healthy mice. Total urinary excretion of OTA increased from 24.41 {plus minus} 1.74 to 40.07 {plus minus} 9.19 μg in NASH mice and kidney-bound OTA decreased ~30%. Renal OAT isoform expression (OAT1-5) in NASH mice decreasd by ~50% with reduced OTA uptake by proximal convoluted cells. These data suggest that NASH-induced OAT transporter reductions attenuate renal secretion and reabsorption of OTA, increasing OTA urinary excretion and reducing renal exposure, thereby reducing nephrotoxicity in NASH.

Significance Statement These data suggest a disease-mediated transporter mechanism of altered tissue-specific toxicity following mycotoxin exposure, despite minimal systemic changes to OTA concentrations. Further studies are warranted to evaluate the clinical relevance of this functional model and the potential effect of human NASH on OTA and other organic anion substrate toxicity.

  • nephrotoxicity
  • organic anion transport
  • renal transport
  • toxicokinetics
  • Copyright © 2020 American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 51 (2)
Drug Metabolism and Disposition
Vol. 51, Issue 2
1 Feb 2023
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NASH increases ochratoxin A renal clearance

Joseph L. Jilek, Kayla L. FROST, Solène MARIE, Cassandra M. MYERS, Michael GOEDKEN, Stephen H. Wright and Nathan J. CHERRINGTON
Drug Metabolism and Disposition December 17, 2021, DMD-MR-2021-000451; DOI: https://doi.org/10.1124/dmd.121.000451

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NASH increases ochratoxin A renal clearance

Joseph L. Jilek, Kayla L. FROST, Solène MARIE, Cassandra M. MYERS, Michael GOEDKEN, Stephen H. Wright and Nathan J. CHERRINGTON
Drug Metabolism and Disposition December 17, 2021, DMD-MR-2021-000451; DOI: https://doi.org/10.1124/dmd.121.000451
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