Molecular Mechanisms for the Selective Transport of Dichlorofluorescein by Human Organic Anion Transporting Polypeptide 1B1.

Autor:	Liu H; College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China (H.L., L.L., T.L., R.H., C.G.); and Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (B.H.)., Li L; College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China (H.L., L.L., T.L., R.H., C.G.); and Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (B.H.)., Liang T; College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China (H.L., L.L., T.L., R.H., C.G.); and Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (B.H.)., Huan R; College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China (H.L., L.L., T.L., R.H., C.G.); and Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (B.H.)., Hagenbuch B; College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China (H.L., L.L., T.L., R.H., C.G.); and Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (B.H.)., Gui C; College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China (H.L., L.L., T.L., R.H., C.G.); and Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (B.H.) guichunshan@suda.edu.cn.
Jazyk:	angličtina
Zdroj:	Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2024 Oct 16; Vol. 52 (11), pp. 1323-1331. Date of Electronic Publication: 2024 Oct 16.
DOI:	10.1124/dmd.124.001853
Abstrakt:	Human organic anion transporting polypeptide (OATP) 1B1 and 1B3 are two highly homologous liver-specific uptake transporters. However, 2',7'-dichlorofluorescein (DCF) is preferably transported by OATP1B1. In the present study, the molecular mechanisms for the selective transport of DCF by OATP1B1 were investigated by constructing and characterizing an array of OATP1B1/1B3 chimeras and site-directed mutagenesis. Our results show that transmembrane domain (TM) 10 is crucial for the surface expression and function of OATP1B1, in which Q541 and L545 play the most important roles in DCF transport. Replacement of TM10 in OATP1B1 with its OATP1B3 counterpart led to OATP1B1's complete intracellular retention. Q541 and L545 may interact with DCF directly via hydrogen bonding and hydrophobic interactions. The decrease of DCF uptake by Q541A and L545S was due to their reduced binding affinity for DCF as compared with OATP1B1. In addition, Q541 and L545 are also crucial for the transport of estradiol-17 β -glucuronide (E17 β G) but not for the transport of estrone-3-sulfate (E3S), indicating different interaction modes between DCF/E17 β G and E3S in OATP1B1. Taken together, Q541 and L545 in TM10 are critical for OATP1B1-mediated DCF uptake, but their effect is substrate-dependent. SIGNIFICANCE STATEMENT: The key TMs and amino acid residues for the selective transport of DCF by OATP1B1 were identified. TM10 is crucial for the surface expression and function of OATP1B1. Within TM10, Q541 and L545 played the most significant roles and affected the function of OATP1B1 in a substrate-dependent manner. This information is crucial for a better understanding of the mechanism of the multispecificity of OATP1B1 and as a consequence the mechanism of OATP1B1-mediated drug-drug interactions. (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu