The uptake mechanism of gallium-67 into hepatocytes treated with carbon tetrachloride

We have recently reported that transferrin (Tf)-unbound gallium-67 (Ga-67) 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 Ga-67 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 Ga-67 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 Ga-67 by PVH treated with CCl4 was also higher than that by PPH. Moreover, the uptake of Ca-45 by PVH was higher than that by PPH. In order to investigate whether Ga-67 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 Ca-45 and Ga-67 by PPH and PVH pretreated with CCl4. The addition of the Ca(2+)channel activator, Bay K8644, significantly increased the uptake both of Ca-45 and Ga-67 by PPH pretreated with CCl4. In the present study, it was demonstrated that the uptake of Tf-unbound Ga-67 preferentially occurred in CCl4-damaged PVH and Ga-67 was taken up into the hepatocytes in part through calcium channel.