RT Journal Article SR Electronic T1 Attenuated Ochratoxin A Transporter Expression in a Mouse Model of Nonalcoholic Steatohepatitis Protects against Proximal Convoluted Tubule Toxicity. JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP DMD-MR-2021-000451 DO 10.1124/dmd.121.000451 A1 Joseph L. Jilek A1 Kayla L. FROST A1 Solène MARIE A1 Cassandra M. MYERS A1 Michael GOEDKEN A1 Stephen H. Wright A1 Nathan J. CHERRINGTON YR 2021 UL http://dmd.aspetjournals.org/content/early/2021/12/17/dmd.121.000451.abstract AB 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.