[Analysis of xenobiotic detoxification system mediated by efflux transporters].
The excretion of drugs mediated by transporters plays an important role in the detoxification of xenobiotics. In this article, I will summarize recent progress we have made in this field, particularly focusing on the roles of transporters responsible for exporting drugs. As far as the biliary excretion of xenobiotics is concerned, it has been suggested that canalicular multispecific organic anion transporter/multidrug resistance associated protein 2 (cMOAT/MRP2) is involved in the ATP-dependent export of organic anions across the bile canalicular membrane. By comparing the transport across this membrane between normal rats and Eisai hyperbilirubinemic rats whose cMOAT/MRP2 function is hereditarily defective, we were able to demonstrate the substrate specificity of cMOAT/MRP2. This includes non-conjugated anionic drugs, and glutathione- and glucuronide-conjugates of xenobiotics. The role of cMOAT/MRP2 in drug disposition has also been clarified. Moreover, the cDNA of cMOAT/MRP2 has been cloned and its functional analysis has been completed. Thus, it may be possible to predict in vivo transport across the bile canalicular membrane from in vitro data using the recombinant transporter. We also cloned MRP3 as an inducible transporter in the liver under the cholestatic conditions. Although MRP3 mediates the cellular export of non-conjugated organic anions and glucuronide-conjugates, the substrate specificity of MRP3 is different from that of cMOAT/MRP2 in that glutathione-conjugates are poor substrates for MRP3. It is possible that MRP3 plays an important role under certain pathological conditions in the liver. Since it has been shown that cMOAT/MRP2 and MRP 3 are expressed in the small intestine under physiological conditions, it seems reasonable that these transporters are responsible for the previously reported cellular extrusion of organic anions. We also found that there was MRP activity in the blood-brain and blood-cerebrospinal fluid barriers. RT-PCR resulted in the amplification of MRP1, 5 and 6 from freshly isolated rat cerebral endothelial cells. It has been suggested that there is basolateral localization of MRP1 in the choroid plexus. In conjunction with the P-glycoprotein located on the luminal membrane of cerebral endothelial cells, these transporters play significant roles in restricting the entry of xenobiotics from the circulating blood into the central nervous system. Regulation of the activity of these efflux transporters allows the disposition of drugs to be altered.
Suzuki
H
H
Graduate School of Pharmaceutical Sciences, University of Tokyo, Japan.
D018528:ATP-Binding Cassette Transporters / Q000502:physiology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D027321:Anion Transport Proteins; D001646:Bile / Q000378:metabolism; D001692:Biological Transport; D001812:Blood-Brain Barrier; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D003001:Cloning, Molecular; D004247:DNA; D008658:Inactivation, Metabolic; D008099:Liver / Q000378:metabolism; D024101:Mitochondrial Proteins; D051381:Rats; D012269:Ribosomal Proteins / Q000235:genetics / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins; D015262:Xenobiotics / Q000493:pharmacokinetics*
D018528:ATP-Binding Cassette Transporters; D027321:Anion Transport Proteins; D002352:Carrier Proteins; C093947:MRP2 protein, S cerevisiae; D024101:Mitochondrial Proteins; D012269:Ribosomal Proteins; D029701:Saccharomyces cerevisiae Proteins; D015262:Xenobiotics; D000255:Adenosine Triphosphate; D004247:DNA