Human organic anion transporting polypeptide (OATP) 1B3 and mouse OATP1A/1B affect liver accumulation of Ochratoxin A in mice.

Abstract

Ochratoxin A (OTA) is a dietary mycotoxin that can cause nephrotoxicity, hepatotoxicity, neurotoxicity and carcinogenicity. We found that in mice OTA is transported by the drug transporters mouse (m)ABCB1 and/or mABCG2, mOATP1A/1B, and human (h)OATP1B3. The complete deletion of mABCB1 and mABCG2 resulted in ~2-fold higher OTA liver and kidney accumulation upon intravenous injection. Upon oral administration, absence of mOATP1A/1B led to a substantial (>3-fold) decrease in hepatic and small intestinal exposure of OTA. Furthermore, in humanized mouse strains, hepatic expression of transgenic hOATP1B3, but not hOATP1B1, partly reversed the reduced liver concentration of OTA in mOATP1A/1B knockout mice. These data indicate that transgenic hOATP1B3 can significantly transport OTA into the liver, and can at least partly compensate for the loss of the mOATP1A/1B transporters. This study shows that some ABC and OATP transporters can substantially affect the pharmacokinetics of OTA, which might have implications for its toxicity behavior.