title: Transport of N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine, a metabolite of trichloroethylene, by mouse multidrug resistance associated protein 2 (Mrp2).
abstract: N-acetyl-S-(1,2-dichlorovinyl)-l-cysteine (Ac-DCVC) and S-(1,2-dichlorovinyl)-l-cysteine (DCVC) are the glutathione conjugation pathway metabolites of a common industrial contaminant and potent nephrotoxicant trichloroethylene (TCE). Ac-DCVC and DCVC are accumulated in the renal proximal tubule where they may be secreted into the urine by an unknown apical transporter(s). In this study, we explored the hypothesis that the apical transport of Ac-DCVC and/or DCVC may be mediated by the multidrug resistance associated protein 2 (Mrp2, ABCC2), which is known to mediate proximal tubular apical ATP-dependent transport of glutathione and numerous xenobiotics and endogenous substances conjugated with glutathione. Transport experiments using membrane vesicles prepared from mouse proximal tubule derived cells expressing mouse Mrp2 utilizing ATPase assay and direct measurements of Ac-DCVC/DCVC using liquid chromatography/tandem mass-spectrometry (LC/MS/MS) demonstrated that mouse Mrp2 mediates ATP-dependent transport of Ac-DCVC. Expression of mouse Mrp2 antisense mRNA significantly inhibited the vectorial basolateral to apical transport of Ac-DCVC but not DCVC in mouse proximal tubule derived cells endogenously expressing mouse Mrp2. The results suggest that Mrp2 may be involved in the renal secretion of Ac-DCVC.
authors.affiliation: Department of Medicine/Nephrology, David Geffen School of Medicine, University of California at Los Angeles, CA 90095, USA.
authors.forename: Kirill
authors.initials: K
authors.lastname: Tsirulnikov
authors.forename: Natalia
authors.initials: N
authors.lastname: Abuladze
authors.forename: Myong-Chul
authors.initials: MC
authors.lastname: Koag
authors.forename: Debra
authors.initials: D
authors.lastname: Newman
authors.forename: Karoline
authors.initials: K
authors.lastname: Scholz
authors.forename: Galyna
authors.initials: G
authors.lastname: Bondar
authors.forename: Quansheng
authors.initials: Q
authors.lastname: Zhu
authors.forename: Nuraly K
authors.initials: NK
authors.lastname: Avliyakulov
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Dekant
authors.forename: Kym
authors.initials: K
authors.lastname: Faull
authors.forename: Ira
authors.initials: I
authors.lastname: Kurtz
authors.forename: Alexander
authors.initials: A
authors.lastname: Pushkin
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D002478:Cells, Cultured; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D051379:Mice; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D022161:Transport Vesicles / Q000737:chemistry / Q000378:metabolism; D014241:Trichloroethylene / Q000378:metabolism / Q000493:pharmacokinetics*; D050988:Vesicle-Associated Membrane Protein 2 / Q000235:genetics / Q000493:pharmacokinetics*
chemical_list: D000111:Acetylcysteine; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger; D014241:Trichloroethylene; D050988:Vesicle-Associated Membrane Protein 2; C494808:vesicle-associated membrane protein 2, mouse; C049705:S-1,2-dichlorovinyl-N-acetylcysteine