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Protection against aflatoxin B1-induced hepatic toxicity as short-term screen of cancer chemopreventive
Y Y Maxuitenko1, T J Curphey, T W Kensler
1Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.
Abstract:
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 micrograms/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.
Insights
Dithiolethiones show promise as cancer chemopreventive agents. Their ability to reduce liver damage from aflatoxin B1 correlates with protection against carcinogenicity, offering a screening method.
Area of Science:
- Chemoprevention
- Hepatotoxicity
- Carcinogenicity
Background:
- Dithiolethiones are recognized for their cancer chemopreventive potential.
- Over 50 novel dithiolethione analogs were synthesized for structure-activity relationship studies.
Purpose of the Study:
- To evaluate the chemopreventive efficacy of dithiolethiones against aflatoxin B1 (AFB1)-induced hepatotoxicity and carcinogenicity.
- To establish a correlation between protection against liver toxicity and carcinogenicity.
Main Methods:
- Rats were pretreated with dithiolethiones and challenged with AFB1.
- Hepatotoxicity was assessed via serum hepatic enzymes, necrosis, and bile duct cell proliferation.
- Carcinogenicity was evaluated by quantifying placental glutathione S-transferase (GST-P)-positive foci.
Main Results:
- Significant correlations (p < 0.01) were found between hepatotoxicity indices and GST-P focal burden.
- Hepatotoxicity markers like alanine aminotransferase (r = 0.943) and histological index (r = 0.893) strongly correlated with protection.
- Bile duct cell proliferation also showed a high correlation (r = 0.933).
Conclusions:
- Inhibition of AFB1-induced hepatotoxicity is linked to protection against hepatocarcinogenicity.
- Assessing acute hepatotoxicity provides a viable short-term screening method for dithiolethiones' chemopreventive properties.
