PROTECTION AGAINST AFLATOXIN B-1-INDUCED HEPATIC TOXICITY AS A SHORT-TERM SCREEN OF CANCER CHEMOPREVENTIVE DITHIOLETHIONES

Dithiolethiones are an important class of cancer chemopreventive agent s. More than 50 new dithiolethione analogs were synthesized for struct ure-activity studies. Using selected dithiolethiones, studies were des igned to measure protection against the hepatotoxicity of aflatoxin B- 1 (AFB(1)) and relate it to the protection against carcinogenicity. Yo ung male F344 rats were pretreated with 0.1 or 0.3 mmol dithiolethione s/kg body wt and challenged with toxic doses of AFB(1) (50 mu g/100 g rat/day) on 2 successive days. One day later, the protection from hepa totoxicity was assessed by measuring serum hepatic enzymes, hepatic ne crosis, and degree of bile duct cell proliferation. The ability of the se dithiolethiones to prevent AFB(1)-induced tumorigenicity was assess ed by quantify the hepatic burden of putative preneoplastic lesions [p lacental glutathione S-transferase (GST-P)-positive foci]. Significant correlations (p < 0.01) were observed between these toxicological ind ices and GST-P focal burden (alanine aminotransferase, r = 0.943; sorb itol dehydrogenase, r = 0.897; histological index r = 0.593; bile duct cell proliferation, r = 0.933), These results imply that inhibition o f hepatotoxicity affords protection against hepatocarcinogenicity, The extent of protection from acute hepatotoxicity offers a simple, short -term biological endpoint to screen dithiolethiones and related compou nds for their chemopreventive properties. (C) 1996 Society of Toxicolo gy