The uptake mechanism of gallium-67 into hepatocytes treated with carbon tetrachloride.
We have recently reported that transferrin (Tf)-unbound gallium-67 (67Ga) may be taken up into the liver of carbon tetrachloride (CCl4)-treated rats. In the present study, we attempted to clarify detailed mechanism of Tf-unbound 67Ga uptake by hepatocytes treated with CCl4 using in vitro experimental system. Hepatotoxic damages by CCl4 are mostly attributed to radical formed by an action of cytochrome P450. P450 isozymes have a higher expression in the perivenous hepatocytes (PVH) more than periportal hepatocytes (PPH). Therefore, we thought that the uptake of 67Ga which had been used for the detection of liver damage might have a zonal difference. The results of ALT activities showed that the CCl4 exposure for 4 h strongly impaired PVH more than PPH. The uptake of 67Ga by PVH treated with CCl4 was also higher than that by PPH. Moreover, the uptake of 45Ca by PVH was higher than that by PPH. In order to investigate whether 67Ga passed through calcium channel of hepatocytes, we made use of calcium channel blocker and activator. The Ca2+-channel blocker, verapamil, significantly decreased the uptakes of 45Ca and 67Ga by PPH and PVH pretreated with CCl4. The addition of the Ca2+-channel activator, Bay K8644, significantly increased the uptake both of 45Ca and 67Ga by PPH pretreated with CCl4. In the present study, it was demonstrated that the uptake of Tf-unbound 67Ga preferentially occurred in CCl4-damaged PVH and 67Ga was taken up into the hepatocytes in part through calcium channel.
Abe
Shinya
S
Department of Radiopharmacy, Tohoku Pharmaceutical University, Miyagi, Japan. shin-abe@tohoku-pharm.ac.jp
Suyama
Satoko
S
Chiba
Seiko
S
Nakao
Hajime
H
Ohtake
Yosuke
Y
Ohkubo
Yasuhito
Y
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D002132:Calcium Radioisotopes / Q000378:metabolism; D002251:Carbon Tetrachloride / Q000633:toxicity*; D002478:Cells, Cultured; D017364:Collagenases / Q000494:pharmacology; D004072:Digitonin / Q000494:pharmacology; D005710:Gallium Radioisotopes / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D014700:Verapamil / Q000494:pharmacology
D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002132:Calcium Radioisotopes; D005710:Gallium Radioisotopes; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D014700:Verapamil; D002251:Carbon Tetrachloride; D000410:Alanine Transaminase; D017364:Collagenases; D004072:Digitonin