In Vitro Detection of Differential and Cell-Specific Hepatobiliary Toxicity Induced by Geldanamycin and 17-Allylaminogeldanamycin Using Dog Liver Slices

Abstract

Experiments on rat liver slices demonstrated the differential hepatobiliary toxic potency of two anticancer agents, geldanamycin (GEL) and 17-allylaminogeldanamycin (17-AAG), over a 5-day period. This report describes the pattern of toxicity of these agents in dog liver tissue, using the in vitro liver slice culture model. Liver slices (200 microm thick) from male beagle dogs were cultured for 5 days in chemically defined culture medium containing a range of GEL and 17-AAG concentrations (0.1-5 microM). Tissues were evaluated using a panel of clinically relevant biomarkers and histological endpoints. GEL-induced reduction of alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) slice levels, indicators of biliary epithelial cell (BEC) viability, was supported by histological findings showing an increasing loss of BEC as higher concentrations were applied. At the highest concentrations studied, GEL caused both hepatocellular necrosis and BEC loss. Biomarker pattern results in the medium concurred with those from slice biochemistry measurements and histology. 17-AAG, a less potent compound in vivo, elicited more biomarker retention at higher concentrations than did GEL. Histological analysis revealed higher BEC viability and significant retention of BEC proliferation as compared with GEL. However, at the highest concentration, the toxic insult caused a marked decrease in BEC viability and proliferation. Comparison of responses with both compounds indicated that slices exposed to the same concentrations were more sensitive to GEL than to 17-AAG. Dog liver slices can thus be used to evaluate species-, compound-, and concentration-dependent differences in toxicity.