Toxicological Sciences 69, 460-469 (2002)
Copyright © 2002 by the Society of Toxicology
SYSTEMS TOXICOLOGY |
Effect of Cadmium on Bromosulfophthalein Kinetics in the Isolated Perfused Rat Liver System
,1
* ManTech Environmental Technology, Dayton, Ohio 45433-7400;
Department of Physics, Wright State University, Dayton, Ohio 45324; and
Operational Toxicology Branch, Air Force Research Laboratory, Bldg. 79, 2856 G St., Wright Patterson Air Force Base, Ohio 45433-7400
Bromosulfophthalein (BSP) is a relatively nontoxic organic anion used as an in vivo indicator of liver performance. Elimination of BSP via the biliary system following iv injection requires dissociation from albumin in plasma, translocation across the sinusoidal membrane, conjugation with glutathione within the hepatocyte, translocation across the bile canalicular membrane, and excretion in bile. The effects of cadmium (Cd), anin vivo hepatotoxicant in rats, on BSP kinetics in the isolated perfused rat liver (IPRL) were studied to investigate the interaction between liver toxicity and BSP kinetics. Livers were isolated from male Fisher 344 rats. After a 30-min period for acclimation to the IPRL system, livers were dosed with Cd (as cadmium acetate), in the presence of 0.25% bovine serum albumin, to give initial concentrations of 10 and 100 µM. Sixty min after Cd dosing, the IPRL system was dosed with BSP to give an initial concentration of 150 µM and the elimination kinetics of BSP from the perfusion medium were monitored. Cadmium concentrations in livers at the end of the experiments were 60 ± 4 and 680 ± 210 µmol/kg for the 10 and 100 µM doses, respectively. Exposure to 10 µM Cd for 60 min resulted in a reduction in bile flow, no significant effect on lactate dehydrogenase (LDH) leakage, and slight effects on BSP clearance. Similar studies following exposure to 100 µM Cd showed a dramatic decrease in bile flow with complete cholestasis 60 min after Cd addition. LDH leakage into perfusion medium at the end of the experiment was less than 10%, indicating that Cd affected bile production well before the liver showed significant signs of necrosis. Clearance of BSP from the perfusion medium was dramatically reduced. Taken together, the data indicate that Cd has a significant effect on the kinetics of BSP in the IPRL and the dominant effects were mediated through the cholestatic effect of Cd.
Key Words: cadmium; bromosulfophthalein; isolated perfused rat liver; biokinetics; cholestasis.
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