Wang Zhongmin, Li Ying, Peng Taotao, Su Ying, Luo Xiaoting, Han Wanjun, Zhang Hongjian, Ruan Jianqing, Gui Chunshan
College of Pharmaceutical Sciences, Soochow University, 199 Renai Road, Suzhou Industrial Park, Suzhou 215123, China.
ACS Omega. 2021 Dec 16;6(51):35844-35851. doi: 10.1021/acsomega.1c06163. eCollection 2021 Dec 28.
Phenolsulfonphthalein (PSP or phenol red), a sulfonphthalein dye, has been used as a diagnostic agent and a pH indicator in cell culture medium. After administered into the body, PSP is excreted into urine and bile. The urinary excretion of PSP is mediated by organic anion transporter 1/3 (OAT1/3) and multidrug resistance protein 2 (MRP2). In biliary excretion, PSP is effluxed from hepatocytes into the bile via MRP2. However, so far, the molecular mechanism for PSP transport from the blood into hepatocytes is unclear. In the present study, six human major hepatic uptake transporters expressed on the basolateral membrane of hepatocytes, namely, organic anion transporting polypeptide 1B1 (OATP1B1), OATP1B3, OATP2B1, Na/taurocholate cotransporting polypeptide (NTCP), organic cation transporter 1 (OCT1), and OAT2, have been investigated to see whether they are involved in the hepatic uptake of PSP. An cell-based study demonstrated that PSP is a substrate for OATP1B1, OATP1B3, and OATP2B1, with OATP1B3 showing the highest transport efficiency. The values for OATP1B1-, OATP1B3-, and OATP2B1-mediated PSP uptake were 11.3 ± 1.5, 7.0 ± 1.5, and 5.1 ± 1.0 μM, respectively. PSP interacts with known OATP substrates/inhibitors. However, the presence of PSP in cell culture medium has no significant effect on OATP's function. pharmacokinetic study in wild-type and Oatp1b2-knockout mice showed that Oatp1b2-knockout led to elevated plasma concentration and decreased liver accumulation of PSP. Taken together, the present study showed that in the liver, OATP1B1, OATP1B3, and OATP2B1 are involved in the uptake of PSP from the blood into hepatocytes, which, along with MRP2-mediated efflux of PSP from hepatocytes into the bile, constitute the vectorial transport of PSP from the blood to the bile and may play a critical role in the biliary excretion of PSP.
酚红（PSP或酚磺酞）是一种磺酞染料，在细胞培养基中用作诊断试剂和pH指示剂。注入体内后，PSP会排泄到尿液和胆汁中。PSP的尿排泄由有机阴离子转运体1/3（OAT1/3）和多药耐药蛋白2（MRP2）介导。在胆汁排泄中，PSP通过MRP2从肝细胞排入胆汁。然而，到目前为止，PSP从血液转运到肝细胞的分子机制尚不清楚。在本研究中，对六种在肝细胞基底外侧膜上表达的人类主要肝脏摄取转运体进行了研究，即有机阴离子转运多肽1B1（OATP1B1）、OATP1B3、OATP2B1、钠/牛磺胆酸盐共转运多肽（NTCP）、有机阳离子转运体1（OCT1）和OAT2，以确定它们是否参与PSP的肝脏摄取。一项基于细胞的研究表明，PSP是OATP1B1、OATP1B3和OATP2B1的底物，其中OATP1B3表现出最高的转运效率。OATP1B1、OATP1B3和OATP2B1介导的PSP摄取的米氏常数分别为11.3±1.5、7.0±1.5和5.1±1.0μM。PSP与已知的OATP底物/抑制剂相互作用。然而，细胞培养基中PSP的存在对OATP的功能没有显著影响。在野生型和Oatp1b2基因敲除小鼠中的药代动力学研究表明，Oatp1b2基因敲除导致PSP的血浆浓度升高和肝脏蓄积减少。综上所述，本研究表明，在肝脏中，OATP1B1、OATP1B3和OATP2B1参与了PSP从血液到肝细胞的摄取，这与MRP2介导的PSP从肝细胞到胆汁的外排一起，构成了PSP从血液到胆汁的向量转运，并可能在PSP的胆汁排泄中起关键作用。
