Transport of N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine, a metabolite of trichloroethylene, by mouse multidrug resistance associated protein 2 (Mrp2)

Journal Article · Thu Apr 15 00:00:00 EDT 2010 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2009.12.035· OSTI ID:21344923

Tsirulnikov, Kirill; Abuladze, Natalia; Koag, Myong-Chul; Newman, Debra ^[1]; Scholz, Karoline ^[2]; Bondar, Galyna; Quansheng, Zhu ^[1]; Avliyakulov, Nuraly K ^[3]; Dekant, Wolfgang ^[2]; Faull, Kym ^[4]; Kurtz, Ira ^[1]; Pushkin, Alexander ^[1]

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1. Department of Medicine/Nephrology, David Geffen School of Medicine, University of California at Los Angeles, CA 90095 (United States)
2. Department of Toxicology, University of Wuerzburg, Wuerzburg (Germany)
3. Department of Biological Chemistry, David Geffen School of Medicine, University of California at Los Angeles, CA 90095 (United States)
4. Pasarow Mass Spectrometry Laboratory, David Geffen School of Medicine, University of California at Los Angeles, CA 90095 (United States)

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.

• OSTI ID: 21344923
• Journal Information: Toxicology and Applied Pharmacology, Vol. 244, Issue 2; Other Information: DOI: 10.1016/j.taap.2009.12.035; PII: S0041-008X(09)00542-0; Copyright (c) 2009 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ATP
CYSTEINE
GLUTATHIONE
HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY
MASS SPECTROSCOPY
MEMBRANES
MESSENGER-RNA
METABOLITES
MICE
ORGANIC CHLORINE COMPOUNDS
TUBULES
URINE
AMINO ACIDS
ANIMALS
BIOLOGICAL MATERIALS
BIOLOGICAL WASTES
BODY
BODY FLUIDS
CARBOXYLIC ACIDS
CHROMATOGRAPHY
DRUGS
KIDNEYS
LIQUID COLUMN CHROMATOGRAPHY
MAMMALS
MATERIALS
NUCLEIC ACIDS
NUCLEOTIDES
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC HALOGEN COMPOUNDS
ORGANIC SULFUR COMPOUNDS
ORGANS
PEPTIDES
POLYPEPTIDES
PROTEINS
RADIOPROTECTIVE SUBSTANCES
RESPONSE MODIFYING FACTORS
RNA
RODENTS
SEPARATION PROCESSES
SPECTROSCOPY
THIOLS
VERTEBRATES
WASTES