Monocarboxylate transporter mediates uptake of lovastatin acid in rat cultured mesangial cells.
To clarify the uptake mechanism(s) for statins, we examined whether monocarboxylate transporter (MCT) contributed to the uptake of lovastatin acid by rat cultured mesangial cells. Expression of mRNAs for MCT1, 2, and 4 was confirmed in mesangial cells. The uptake of lovastatin acid by mesangial cells increased with decreasing extracellular pH. There was clear overshooting in lovastatin acid uptake by the ATP-depleted cells in the presence, but not in the absence, of an inwardly directed H(+)-gradient. The representative MCT substrates/inhibitors inhibited the lovastatin acid uptake. In particular, the inhibition of lovastatin acid uptake by L-lactic acid at the concentration of 80 mM reached 70%, and L-lactic acid and valproic acid inhibited the uptake competitively. On preloading of mesangial cells with L-lactic acid or valproic acid, the lovastatin acid uptake was significantly stimulated. The inhibition constant of L-lactic acid for the lovastatin acid uptake was 32 mM, and this value is comparable to the Michaelis constant (>20 mM) of L-lactic acid for MCT4 described elsewhere. These results demonstrate that lovastatin acid was largely taken up by mesangial cells via MCT, and suggest that MCT4 might contribute to lovastatin acid uptake in the cells.
Nagasawa
Kazuki
K
Department of Environmental Biochemistry, Kyoto Pharmaceutical University, 5, Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan. nagasawa@mb.kyoto-phu.ac.jp
Nagai
Katsuhito
K
Sumitani
Yuji
Y
Moriya
Yuka
Y
Muraki
Yuichi
Y
Takara
Kohji
K
Ohnishi
Noriaki
N
Yokoyama
Teruyoshi
T
Fujimoto
Sadaki
S
D000818:Animals; D002478:Cells, Cultured; D005920:Glomerular Mesangium / Q000166:cytology / Q000378:metabolism*; D008148:Lovastatin / Q000493:pharmacokinetics*; D008297:Male; D027501:Monocarboxylic Acid Transporters / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D027501:Monocarboxylic Acid Transporters; D020033:Protein Isoforms; D012333:RNA, Messenger; D008148:Lovastatin