Human organic anion transporting polypeptide (OATP) 1B3 and mouse OATP1A/1B affect liver accumulation of Ochratoxin A in mice
Autor: | Maria C. Lebre, Xiaozhe Qi, Jing Wang, Alfred H. Schinkel, Changpei Gan |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Ochratoxin A Male Organic Cation Transport Proteins Mice Transgenic Pharmacology Toxicology Nephrotoxicity 03 medical and health sciences chemistry.chemical_compound Mice Solute Carrier Organic Anion Transporter Family Member 1B3 0302 clinical medicine medicine Animals Humans Carcinogen Mice Knockout biology Chemistry Liver-Specific Organic Anion Transporter 1 Neurotoxicity food and beverages medicine.disease Calcium Channel Blockers Ochratoxins Organic anion-transporting polypeptide 030104 developmental biology Liver 030220 oncology & carcinogenesis Humanized mouse Toxicity Knockout mouse biology.protein |
Zdroj: | Toxicology and applied pharmacology. 401 |
ISSN: | 1096-0333 |
Popis: | 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. |
Databáze: | OpenAIRE |
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