DOC PREVIEW
UNC-Chapel Hill ENVR 442 - The Role of Transporters (Phase III) in Xenobiotic Disposition

This preview shows page 1-2-16-17-18-34-35 out of 35 pages.

Save
View full document
View full document
Premium Document
Do you want full access? Go Premium and unlock all 35 pages.
Access to all documents
Download any document
Ad free experience
View full document
Premium Document
Do you want full access? Go Premium and unlock all 35 pages.
Access to all documents
Download any document
Ad free experience
View full document
Premium Document
Do you want full access? Go Premium and unlock all 35 pages.
Access to all documents
Download any document
Ad free experience
View full document
Premium Document
Do you want full access? Go Premium and unlock all 35 pages.
Access to all documents
Download any document
Ad free experience
View full document
Premium Document
Do you want full access? Go Premium and unlock all 35 pages.
Access to all documents
Download any document
Ad free experience
View full document
Premium Document
Do you want full access? Go Premium and unlock all 35 pages.
Access to all documents
Download any document
Ad free experience
View full document
Premium Document
Do you want full access? Go Premium and unlock all 35 pages.
Access to all documents
Download any document
Ad free experience
Premium Document
Do you want full access? Go Premium and unlock all 35 pages.
Access to all documents
Download any document
Ad free experience

Unformatted text preview:

K.L.R. Brouwer1September 8, 2009TOXC 442Xenobiotic TransportersBiochemical and Molecular ToxicologyENVR 442/TOXC 442/BIOC 442The Role of Transporters (Phase III)in Xenobiotic DispositionKim L.R. Brouwer, PharmD, PhDWilliam R. Kenan Distinguished Professor and Chair,Division of Pharmacotherapy & Experimental TherapeuticsUNC Eshelman School of [email protected]; 919-962-7030PPPPCOOHNH2PPPPPPPPCOOHNH2Organic Anion TransportersOrganic Anion TransportersSolute Carrier Family 22Solute Carrier Family 22PAH, OTA, DHEA-sulfate, estrone-sulfate, AZT, cimetidine, MTXantiport (dicarboxylates)kidney, placentaOAT4PAH, OTA, salicylate, estrone-sulfate, cAMP, PGE2, cimetidineantiport (dicarboxylates)kidney, liver, bone, brain, eyeOAT3PAH, MTX, salicylate, acetylsalicylate, PGE2?kidney, liverOAT2PAH, PSP, methotrexate (MTX), cidofovir, ochratoxin A (OTA), cephaloridine, indoxyl sulfate, AZT, penicillins, cAMP, cGMP, PGE2, etc.antiport (dicarboxylates)kidney, brain, choroid plexusOAT1SubstratesTransport mechanismTissue distributionTransporterF. RusselK.L.R. Brouwer2September 8, 2009TOXC 442Xenobiotic TransportersOrganic Anion TransportingOrganic Anion TransportingPolypeptidesPolypeptidesSolute Carrier Family 21/SLCOSolute Carrier Family 21/SLCOMTX, folate, DHEA sulfate, E217βG ochratoxin A, digoxin, MTX, AZTBSP, DHEA, estradiol glucuronide, estrone sulfate, thyroxine, T3, ochratoxin A, bile acids, fexofenadine, oubain, rocuronium, chlorambucildigoxin, ouabain, thyroxine, T3, cAMP, MTX?antiport?(GSH)?kidneybrain, kidney, liverkidneyOat-k1/k2 (1a3_v1/v2)OATP-A (1A2)OATP-H (4C1)??kidneyOatp5 (1a6)taurocholate, thyroxine, T3?kidney, lung, retina, liverOatp3 (1a5)BSP,ouabain, taurocholate, estradiol glucuronide (E217βG), estrone sulfate, DHEA sulfate, aldosterone, cortisol, enalapril, thyroxine, triiodo-L-thyronine (T3), leukotriene C4, PGE2, ochratoxin Aantiport(GSH)kidney, liverOatp1 (1a1)SubstratesTransport mechanismTissue distributionTransporterF. RusselOrganic Cation TransportersOrganic Cation TransportersSolute Carrier Family 22Solute Carrier Family 22PPPPCOOHNH2PPPPPPPPCOOHNH2MPP+, guanidine, monoamines, cimetidine, tyramineuniportliver, skeletal muscle, placenta, kidney,heart, brainOCT3TEA, MPP+, carnitine, choline, quinidine, verapamil, pyrilamine, valproateuniport Na+-carnitine cotransportskeletal muscle, kidney, placenta, liver, intestine, heart, etc.OCTN2TEA, MPP+, carnitine, quinidine, verapamil, pyrilamineantiport (H+)kidney, skeletal muscle, placenta, prostate, heartOCTN1TEA, MPP+, NMN, monoamines, amantadineuniportkidney, brain, neuronsOCT2MPP+, TEA, acyclovir, gancicloviruniportliverOCT1SubstratesTransport mechanismTissue distributionTransporterF. RusselK.L.R. Brouwer3September 8, 2009TOXC 442Xenobiotic TransportersBQ123, glutathione conjugatesE217βG, calcein, rhodamine 123, digoxin, anticancer drugs, verapamil, anti-HIV drugs, steroid hormonespump (ATP)pump (ATP)kidney, liverkidney, liver, intestine, brain, placenta, lungMRP6MDR1cidofovir, PMEA, AZTMP, MTX, PAH, cAMP, cGMP, prostaglandinspump (ATP)kidney, liver, intestine, brain, prostateMRP4glutathione, glucuronide, and sulfate conjugates, PAH, GSH, GSSG, cisplatin, methotrexate, ochratoxin Apump (ATP) kidney, liver, intestine MRP2glutathione, glucuronide, and sulfate conjugates, anticancer agents, GSH, GSSG, PAHpump (ATP)kidney, (liver), lung, intestine, brainMRP1SubstratesTransport mechanismTissue distributionTransporterMultidrug Resistance TransportersMultidrug Resistance TransportersATPATP--Binding Cassette subfamily (ABCB/ABCC)Binding Cassette subfamily (ABCB/ABCC)outinNH2COOHATPATPoutinNH2COOHATPATPoutinoutinNH2COOHATPATPoutinoutinNH2COOHATPATPMRP1MRP2MRP6MRP4MRP5MDR1F. RusselAyrton & Morgan, Xenobiotica 31:469, 2001Organ Distribution of Transport Proteins BSEPK.L.R. Brouwer4September 8, 2009TOXC 442Xenobiotic TransportersMdr1a P-gpMdr1b P-gpBBBGallbladderLiverStomachIntestineKidneyAdapted fromSchinkel, 1997Organ Distribution of Multidrug Resistance Mdr1 P-glycoproteinP-gp Expression in Murine Brain Capillary Endothelial CellsGraff and Pollack, 2005K.L.R. Brouwer5September 8, 2009TOXC 442Xenobiotic TransportersIvermectin Toxicity inMdr1a(-/-) and Mdr1a(+/+) MiceSchinkel et al., Cell, 77:491, 1994Maintenance of Barrier Function:Xenobiotic Transporters in the BrainHo and Kim, Clin Pharmacol Ther 78:260, 2005K.L.R. Brouwer6September 8, 2009TOXC 442Xenobiotic TransportersP-glycoprotein stainingEndothelial cell stainingCo-localizationMaintenance of Barrier Function:Endothelial Cells Lining the Olfactory BulbGraff and Pollack, Pharm Res 22:86, 2005Maintenance of Barrier Function in Sanctuary Site TissuesPlacentaLeslie et al., Tox Appl Pharmacol 204:216, 2005K.L.R. Brouwer7September 8, 2009TOXC 442Xenobiotic TransportersMaintenance of Barrier Function:Xenobiotic Transporters in the IntestineHo and Kim, Clin Pharmacol Ther 78:260, 2005Role of Mrp1 in Intestinal Toxicity of MethotrexateIntestinal toxicity induced by methotrexate treatment in wild-type [Mrp1(+/+)] and Mrp1 gene knockout [Mrp1(−/−)] mice in vivo. Mrp1 is localized primarily in proliferative cells in crypts where it is involved in active efflux of methotrexate as a defensive mechanism to protect the small intestinal epithelial cells from toxicity.Tissue sections from ‘lower’ part of the small intestine were analyzed for morphology with H&E staining (top panel) and for S-phase cells with immunostaining using anti-BrdU antibody (bottom panel).Ho and Kim, Clin Pharmacol Ther 78:260, 2005K.L.R. Brouwer8September 8, 2009TOXC 442Xenobiotic TransportersXenobiotic Transporters in the KidneyHo and Kim, Clin Pharmacol Ther 78:260, 2005Effect of Probenecid on Renal Content and Urinary Excretion of Cadmium (Cd) in Mice Mice were injected i.p. with saline or probenecid (1 mmol/kg), and injected i.v. 30 min later with either Cd alone (1 mg Cd/kg, 74 kBq 109Cd) or Cd with dithiocarbamate chelating agents (1:30 molar ratio); urine samples were collected for 3 h and renal Cd content was determined from radioactivity.Kamenosono et al., Comp Biochem Physiol C Toxicol Pharmacol 132:61, 2002K.L.R. Brouwer9September 8, 2009TOXC 442Xenobiotic TransportersOatk1/2Oatk1/2MRP1MRP1PTPTTALTALCDCDrOat2rOat2MRP6MRP6rOat3rOat3Oatp1Oatp1OAT4OAT4OAT1OAT1OAT3OAT3cortexcortexmedullamedullaNephron Distribution of Organic Anion TransportersNephron Distribution of Organic Anion TransportersMRP2MRP2MRP4MRP4Oatv1Oatv1F.


View Full Document

UNC-Chapel Hill ENVR 442 - The Role of Transporters (Phase III) in Xenobiotic Disposition

Documents in this Course
Load more
Download The Role of Transporters (Phase III) in Xenobiotic Disposition
Our administrator received your request to download this document. We will send you the file to your email shortly.
Loading Unlocking...
Login

Join to view The Role of Transporters (Phase III) in Xenobiotic Disposition and access 3M+ class-specific study document.

or
We will never post anything without your permission.
Don't have an account?
Sign Up

Join to view The Role of Transporters (Phase III) in Xenobiotic Disposition 2 2 and access 3M+ class-specific study document.

or

By creating an account you agree to our Privacy Policy and Terms Of Use

Already a member?