Received for publication March 21, 2005.
Revised May 18, 2005.
Accepted for publication May 18, 2005.

Transport of N-Acetylcysteine S-Conjugates of Methylmercury in MDCK Cells Transfected Stably with hOAT1

Abstract

Recent studies have implicated the activity of the organic anion transporter 1 (OAT1) protein in the basolateral uptake of inorganic mercuric species in renal proximal tubular epithelial cells. However, very little is known about the potential role of OAT1 (and other OATs) in the renal epithelial transport of organic forms of mercury such as methylmercury (CH₃Hg⁺). The present investigation was designed to study the transport of NAC S-conjugates of both methylmercury (CH₃Hg-NAC) and inorganic mercury (NAC-Hg-NAC) in renal epithelial cells (Madin- Darby canine kidney (MDCK) cells) transfected stably with the human isoform of OAT1 (hOAT1). These mercuric species were studied because numerous mercapturates have been shown to be substrates of OATs. Data on saturation kinetics, time-dependency, substrate specificity and temperature-dependency for the transport of CH₃Hg-NAC and NAC-Hg-NAC indicate that both of these two mercuric species are indeed transportable substrates of hOAT1. Substrate-specificity data also show that CH₃Hg-NAC is substrate of a transporter in MDCK cells that is not hOAT1. These data indicate that an amino acid carrier system is a likely candidate responsible for this transport. Furthermore, rates of survival of the hOAT1-transfected MDCK cells were significantly lower than those of corresponding control MDCK cells when they were exposed to cytotoxic concentrations of CH₃Hg-NAC or NAC-Hg-NAC. Collectively, the present data support the hypothesis that CH₃Hg-NAC and NAC-Hg-NAC are transportable substrates of OAT1, and thus, are potentially transportable mercuric species taken up in vivo at the basolateral membrane of proximal tubular epithelial cells.

Key words: MDCK Cells, Mercapturic Acid Conjugates of Mercury, Mercury Induced Nephropathy, Methylmercury Transport in Kidney, Organ Anion Transporters, Proximal Tubule

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