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Characterization of ANIT-Induced Toxicity using Precision-Cut Rat and Dog Liver Slices Cultured in a Dynamic Organ Roller System
1 SRI International, Menlo Park, CA 94025, USA Correspondence: Address correspondence to: H. P. Behrsing, HepaHope Inc., 152 W. Technology Dr., Irvine, California 92618, USA; e-mail:behrsing{at}gmail.com
This article describes the toxicity of
Key Words: Alternative models in toxicology • hepatobiliary system • in vitro toxicology • ANIT • liver slices • rat • dog Abbreviations: ANIT,
Toxicologic Pathology, Vol. 34, No. 6,
776-784 (2006) |
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-naphthylisothiocyanate (ANIT), a compound known to induce dose-dependent hepatobiliary toxicity in vivo, using the slice model. Liver slices (200 µm thick) from male Sprague–Dawley rats and male beagle dogs were cultured for 7 days while exposed to a range of ANIT concentrations (1– 100 µM for rat and 4–320 µM for dog). Tissues (and medium for dog) were evaluated using a panel of clinically relevant biomarkers for liver and histological endpoints to assess viability and proliferation. ANIT increased slice levels of enzyme biomarkers corresponding to biliary markers. At high concentrations (80–100 µM for rat, 320 µM for dog) a diminution of tissue enzyme levels was observed, corresponding to severe hepatobiliary injury. By days 5 and 7, biochemical markers in the medium of dog slices indicated an elevation of hepatocellular and biliary markers. Histologically for both species, minimal hepatocellular injury was noted, but proliferation of biliary epithelial cells (BEC) was observed using 5-bromo-2-deoxyuridine (BrdU) immunostaining. In rat slices, ANIT increased the expression of inducible nitrous oxide synthase (iNOS) within 12 hrs of exposure. In summary, additional experimentation using slice culture may further demonstrate its value in screening compounds that cause hepatobiliary toxicity.