Resistance of human brain microvascular endothelial cells in culture to methylmercury: cell-density-dependent defense mechanisms.
Vascular toxicity is important for understanding the neurotoxicity of methylmercury, because microvessels strongly influence the construction of microenvironment around neurons. Previously, we found that low density-human brain microvascular pericytes are markedly susceptible to methylmercury cytotoxicity due to high expression levels of the L-type amino acid transporter 1 (LAT-1) that transports methylmercury into the cells. Although LAT-1 can be, in general, highly expressed in sparse cells that require amino acids for growth, we found that human brain microvascular endothelial cells, regardless of cell density, were resistant to methylmercury cytotoxicity. To investigate the mechanisms underlying this resistance, we exposed the endothelial cells at low and high cell densities to methylmercury and determined the extent of nonspecific cell damage, intracellular accumulation of methylmercury, expression of LAT-1 and LAT-2 mRNAs, and intracellular expression of reduced glutathione and metallothionein. These experiments indicate that sparse endothelial cells intracellularly accumulate more methylmercury via the highly expressed LAT-1, but are resistant to methylmercury cytotoxicity by higher expression of the protective sulfhydryl peptides, namely, reduced glutathione and metallothionein. It is suggested that both nonspecific and functional damage is caused in pericytes, whereas functional abnormalities rather than nonspecific damage may occur to a greater extent in the endothelial cells in the brain microvessels exposed to methylmercury. The previous and present data also suggest that methylmercury exhibits toxicity in endothelial cells in a manner different from that in pericytes in the brain microvessels.
Hirooka
Takashi
T
Organization for Frontier Research in Preventive Pharmaceutical Sciences, Hokuriku University, Kanagawa-machi, Kanazawa, Japan.
Fujiwara
Yasuyuki
Y
Shinkai
Yasuhiro
Y
Yamamoto
Chika
C
Yasutake
Akira
A
Satoh
Masahiko
M
Eto
Komyo
K
Kaji
Toshiyuki
T
D001921:Brain / Q000166:cytology*; D002452:Cell Count; D002478:Cells, Cultured; D004351:Drug Resistance; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D027283:Large Neutral Amino Acid-Transporter 1 / Q000378:metabolism; D008767:Methylmercury Compounds
D027283:Large Neutral Amino Acid-Transporter 1; D008767:Methylmercury Compounds; D005978:Glutathione