Methylmercury transport across the blood-brain barrier by an amino acid carrier.
The mechanism by which methylmercury (MeHg) crosses the blood-brain barrier was examined in the rat. Previous studies demonstrated that intravenous injection of L-cysteine with MeHg accelerates MeHg uptake into brain. Since the complex of MeHg with L-cysteine is structurally similar to L-methionine, a substrate for the L (leucine-preferring) amino acid transport system, this carrier may be involved in MeHg uptake. To examine this hypothesis, the rapid carotid infusion technique was used in the anesthetized rat. The concentration dependence of 203Hg uptake into brain after injection of Me203Hg-L-cysteine complex was nonlinear, exhibiting characteristics of saturable transport (apparent Michaelis constant 0.39 mM, vmax 33 nmol.min-1.g-1). A slower, nonsaturable uptake was seen after MeHg-L-cysteine uptake was inhibited by methionine and the amino acid analogue 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid (BCH), an L system substrate, but not by alpha-methylaminoisobutyric acid, an alanine-preferring system substrate. Furthermore, L-[14C]methionine transport was inhibited by MeHg-L-cysteine but not by MeHgCl. There was a significant amount of uptake of 203Hg when injected as Me203Hg-glutathione, and this was inhibited by L-methionine and BCH but not D-methionine. S-ethylglutathione also inhibited 203Hg uptake after administration as Me203Hg-glutathione but had no effect on Me203Hg-L-cysteine uptake. These results suggest that MeHg may enter the brain as a cysteine complex via the L system and that plasma MeHg-glutathione serves as a source of MeHg-cysteine.
Kerper
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LE
Department of Biophysics, University of Rochester School of Medicine, New York 14642.
Ballatori
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N
Clarkson
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TW
D026905:Amino Acid Transport Systems; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier; D002352:Carrier Proteins / Q000502:physiology*; D003545:Cysteine / Q000493:pharmacokinetics; D005260:Female; D008628:Mercury / Q000493:pharmacokinetics; D008715:Methionine / Q000494:pharmacology; D008767:Methylmercury Compounds / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains
D026905:Amino Acid Transport Systems; D000596:Amino Acids; D002352:Carrier Proteins; D008767:Methylmercury Compounds; D008715:Methionine; D008628:Mercury; D003545:Cysteine