Organic anion transporting polypeptide 1 B1 and 1 B3(OATP1 B1/3)as important uptake transporters play a fundamental role in the transportation of exogenous drugs and endogenous substances into cells.Rat OATP1 B2,encod...Organic anion transporting polypeptide 1 B1 and 1 B3(OATP1 B1/3)as important uptake transporters play a fundamental role in the transportation of exogenous drugs and endogenous substances into cells.Rat OATP1 B2,encoded by the Slcolb2 gene,is homologous to human OATP1 B1/3.Although OATP1 B1/3 is very important,few animal models can be used to study its properties.In this report,we successfully constructed the Slco1 b2 knockout(KO)rat model via using the CRISPR/Cas9 technology for the first time.The novel rat model showed the absence of OATP1 B2 protein expression,with no offtarget effects as well as compensatory regulation of other transporters.Further pharmacokinetic study of pitavastatin,a typical substrate of OATP1 B2,confirmed the OATP1 B2 function was absent.Since bilirubin and bile acids are the substrates of OATP1 B2,the contents of total bilirubin,direct bilirubin,indirect bilirubin,and total bile acids in serum are significantly higher in Slco1 b2 KO rats than the data of wild-type rats.These results are consistent with the symptoms caused by the absence of OATP1 B1/3 in Rotor syndrome.Therefore,this rat model is not only a powerful tool for the study of OATP1 B2-mediated drug transportation,but also a good disease model to study hyperbilirubinemia-related diseases.展开更多
基金supported in whole or part by grants from the National Natural Science Foundation of China(No.81773808)the Science and Technology Commission of Shanghai Municipality(Nos.17140901000,17140901001 and 18430760400)supported from ECNU Multifunctional Platform for Innovation(011,China)
文摘Organic anion transporting polypeptide 1 B1 and 1 B3(OATP1 B1/3)as important uptake transporters play a fundamental role in the transportation of exogenous drugs and endogenous substances into cells.Rat OATP1 B2,encoded by the Slcolb2 gene,is homologous to human OATP1 B1/3.Although OATP1 B1/3 is very important,few animal models can be used to study its properties.In this report,we successfully constructed the Slco1 b2 knockout(KO)rat model via using the CRISPR/Cas9 technology for the first time.The novel rat model showed the absence of OATP1 B2 protein expression,with no offtarget effects as well as compensatory regulation of other transporters.Further pharmacokinetic study of pitavastatin,a typical substrate of OATP1 B2,confirmed the OATP1 B2 function was absent.Since bilirubin and bile acids are the substrates of OATP1 B2,the contents of total bilirubin,direct bilirubin,indirect bilirubin,and total bile acids in serum are significantly higher in Slco1 b2 KO rats than the data of wild-type rats.These results are consistent with the symptoms caused by the absence of OATP1 B1/3 in Rotor syndrome.Therefore,this rat model is not only a powerful tool for the study of OATP1 B2-mediated drug transportation,but also a good disease model to study hyperbilirubinemia-related diseases.
