Role of hepatic transporters in the detoxification

我们attempted to establish gene expression system for several types of transporters expressed in theliver,in Which the功能分析of the hepatobiliary transport of organic compounds can beperformed. We collaborated with Dr. Peter J. Meier and investigated the contribution of organicanion transporters on the sinusoidal membrane such as oatp1 and Ntcp to the net hepatic uptake ofseveral kinds of organic anions by comparing the transport activity between transfectant andcultured rat hepatocytes. The substrate specificity of canalicular multispecific organic aniontransporter (cMOAT) which is known to play a predominant role in the biliay excretion of severalanionic compounds was investigated and folates and its structural analogues as well as smallpeptides with anionic moiety were identified as new substrates of cMOAT. The uptake of organicanions into canalicular membrane vesicles exhibits a large interindividual difference in humans.要,there is a large species difference in the biliary excretion of an angiotensin converting enzymeinhibitor,这是attributed to the species difference in the membrane transport via cMOAT. the presentfindings应该被clinically important for the prediction of drug-drug interactions of these drugsvia the transporters. We investigated the effect of a multidrug resistance modulatorSDZ PSC 833 on the biliary excretion of endogenous compounds and drugs. the analysis usingP-glycoprotein表pression system gifted from Dr. Piet Borst is being carried out. We succeeded toisolate cDNA of MRP3 from the liver of mutant rats which cMOAT is hereditarily deficient，and to characterize its substrate specificity and transport property，MRP3是reported to confer resistance to a certain type of anticancer drugs. The present results应该important to understand the detoxification system in the body and also tumors。

We attempted to establish gene expression system for several types of transporters expressed in the liver, in Which the functional analyses of the hepatobiliary transport of organic compounds can be performed. We collaborated with Dr. Peter J. Meier and investigated the contribution of organic anion transporters on the sinusoidal membrane such as oatp1 and Ntcp to the net hepatic uptake of several kinds of organic anions by comparing the transport activity between transfectant and cultured rat hepatocytes. The substrate specificity of canalicular multispecific organic anion transporter (cMOAT) which is known to play a predominant role in the biliay excretion of several anionic compounds was investigated and folates and its structural analogues as well as small peptides with anionic moiety were identified as new substrates of cMOAT. The uptake of organic anions into canalicular membrane vesicles exhibits a large interindividual difference in humans. Also, there is a large species difference in the biliary excretion of an angiotensin converting enzyme inhibitor, which is attributed to the species difference in the membrane transport via cMOAT. The present findings should be clinically important for the prediction of drug-drug interactions of these drugs via the transporters. We investigated the effect of a multidrug resistance modulator, SDZ PSC 833 on the biliary excretion of endogenous compounds and drugs. The analysis using P-glycoprotein expression system gifted from Dr. Piet Borst is being carried out. We succeeded to isolate cDNA of MRP3 from the liver of mutant rats which cMOAT is hereditarily deficient, and to characterize its substrate specificity and transport property, ・ MRP3 is reported to confer resistance to a certain type of anticancer drugs. The present results should be important to understand the detoxification system in the body and also tumors.