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© 1996 Oxford University Press

research-article

Protection against Aflatoxin B1-Induced Hepatic Toxicity as a Short-Term Screen of Cancer Chemopreventive Dithiolethiones1

YULIA Y. MAXUITENKO*, THOMAS J. CURPHEY{dagger}, THOMAS W. KENSLER{ddagger} and B. D. ROEBUCK*,2

*Department of Pharmacology and Toxicology Dartmouth Medical School Hanover, New Hampshire 03755 {dagger}Department of Pathology, Dartmouth Medical School Hanover, New Hampshire 03755 {ddagger}Department of Environmental Health Sciences, Johns Hopkins School of Hygiene and Public Health Baltimore Maryland 21205

Received February 20, 1996; accepted April 6, 1996

Dithiolethiones are an important class of cancer chemopreventive agents. More than 50 new dithiolethione analogs were synthesized for structure-activity studies. Using selected dithiolethiones, studies were designed to measure protection against the hepatotoxicity of aflatoxin B1 (AFB1) and relate it to the protection against carcinogenicity. Young male F344 rats were pretreated with 0.1 or 0.3 mmol dithiolethiones/kg body wt and challenged with toxic doses of AFB1 (50 µg/100 g rat/day) on 2 successive days. One day later, the protection from hepatotoxicity was assessed by measuring serum hepatic enzymes, hepatic necrosis, and degree of bile duct cell proliferation. The ability of these dithiolethiones to prevent AFB1-induced tumorigenicity was assessed by quantifying the hepatic burden of putative preneoplastic lesions [placental glutathione S-transferase (GST-P)-positive foci]. Significant correlations (p < 0.01) were observed between these toxicological indices and GST-P focal burden (alanine aminotransferase, r = 0.943; sorbitol dehydrogenase, r = 0.897; histological index, r = 0.893; bile duct cell proliferation, r = 0.933). These results imply that inhibition of hepatotoxicity affords protection against hepatocarcinogenicity. The extent of protection from acute hepatotoxicity offers a simple, short-term biological endpoint to screen dithiolethiones and related compounds for their chemopreventive properties.


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