Transport of N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine, a metabolite of trichloroethylene, by mouse multidrug resistance associated protein 2 (Mrp2).
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.
Tsirulnikov
Kirill
K
Department of Medicine/Nephrology, David Geffen School of Medicine, University of California at Los Angeles, CA 90095, USA.
Abuladze
Natalia
N
Koag
Myong-Chul
MC
Newman
Debra
D
Scholz
Karoline
K
Bondar
Galyna
G
Zhu
Quansheng
Q
Avliyakulov
Nuraly K
NK
Dekant
Wolfgang
W
Faull
Kym
K
Kurtz
Ira
I
Pushkin
Alexander
A
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*
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