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• W2100033932 endingPage "1210" @default.
• W2100033932 startingPage "1203" @default.
• W2100033932 abstract "Organic anion transporters (OATs) mediate the body disposition of a diverse array of environmental toxins and clinically important drugs. Previous studies have shown that novobiocin, an inhibitor for breast cancer resistance proteins (BCRP), inhibited organic anion transport. However, its interactions with specific OATs are unknown. In the current study, we characterized the inhibitory effects of novobiocin on the function of human OATs (hOAT)1, hOAT3, and hOAT4. Kinetic study revealed that novobiocin inhibited OAT-mediated uptake in a competitive manner, with K(i) of 14.87 +/- 0.40 microM for hOAT1, K(i) of 4.77 +/- 1.12 microM for hOAT3, and K(i) of 90.50 +/- 7.50 microM for hOAT4. Furthermore, the cis- and trans-inhibition feature of novobiocin demonstrated that novobiocin was a potent inhibitor but not a substrate for hOAT1 (IC(50) = 34.76 +/- 0.31 microM), hOAT3 (IC(50) = 4.987 +/- 0.35 microM), and hOAT4 (IC(50) = 92.68 +/- 0.34 microM). We further showed that the effects of novobiocin on OATs were not mediated through a change in transporter protein abundance on the plasma membrane. Taken together, we conclude that novobiocin seems to interact with the substrate-binding sites of OATs from both the intracellular and the extracellular sides, and this interaction interferes with the substrate-binding site(s) on respective carriers, leading to an apparent reduction in carriers available for the substrates. Because BCRP is often expressed in the same tissue where multiple OATs are identified such as liver, kidney and placenta, when dissecting the contribution of BCRP to drug disposition using novobiocin as an inhibitor, its inhibitory effect to OATs has to be taken into consideration." @default.
• W2100033932 created "2016-06-24" @default.
• W2100033932 creator A5072008267 @default.
• W2100033932 creator A5083159517 @default.
• W2100033932 date "2009-03-12" @default.
• W2100033932 modified "2023-10-17" @default.
• W2100033932 title "Novobiocin Is a Potent Inhibitor for Human Organic Anion Transporters" @default.
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• W2100033932 doi "https://doi.org/10.1124/dmd.109.026880" @default.
• W2100033932 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/2683688" @default.
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• W2100033932 hasPublicationYear "2009" @default.
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