Role of System ATB 0,+ in the Transport of Cysteine S ‐Conjugates of Methylmercury

Abstract

Methylmercury (CH3Hg) is a clinically relevant toxicant that is the most abundant form of mercury found in the environment. Once ingested, it accumulates in the liver, kidneys and central nervous system. The mechanisms by which this toxicant is taken up by target cells are only now beginning to be understood. Some experimental data support a hypothesis involving molecular mimicry, whereby a thiol-conjugate of methylmercury, especially a cysteine S-conjugate, mimics an amino acid, such as methionine, and is transported into the target cells by one or more amino acid transporter(s). In the present study, we tested the hypothesis that the cysteine (Cys) S-conjugate of methylmercury (CH3Hg-S-Cys) mimics an amino acid at the site of system ATB0,+, which in the kidneys, is situated on the luminal plasma membrane of proximal tubular epithelial cells. To test this hypothesis, we measured the uptake of 14C-CH3Hg-S-Cys into Xenopus laevis oocytes injected with cRNA encoding mouse ATB0,+. Time-course, substrate-specificity and saturation kinetic analyses showed that the uptake of CH3Hg-S-Cys was 5–10-fold greater in oocytes injected with ATB0,+ than in water-injected controls. The transport of CH3Hg-S-Cys was inhibited by substrates of system ATB0,+. These data indicate that CH3Hg-S-Cys may act as a mimic of an amino acid that is normally transported by system ATB0,+. To our knowledge, this is the first report implicating system ATB0,+ in the Na+-dependent transport of CH3Hg-S-Cys.