Hepatocellular carcinoma has one of the poorest 5 year survival rates of any human
cancer. Preventive measures offer the best possibility of ameliorating this disease and chemoprotective agents are being developed for this purpose. The dithiolethiones, including
oltipraz and the unsubstituted molecule
1,2-dithiole-3-thione, have been shown to be potent inhibitors of
aflatoxin-induced hepatic
tumorigenesis in rats. However, subsequent evaluation of dithiolethiones or other chemoprotective agents in human clinical trials will require the development of intermediate, non-invasive
biomarkers to evaluate the efficacy of these interventions. In this study, levels of molecular dosimetry
biomarkers for determining genotoxic damage caused by
aflatoxin B1 have been measured in a chronic exposure model with male F344 rats wherein half the animals were fed a diet supplemented with 0.03%
1,2-dithiole-3-thione to lower their risk for
tumors and the other half were fed unsupplemented AIN-76A diet and were at high risk for
tumor development. Levels of hepatic
aflatoxin-
DNA adducts, serum
aflatoxin-
albumin adducts and excreted aflatoxin-N7-guanine adducts in urine were determined following multiple administrations of 250 micrograms
aflatoxin B1/kg body wt on days 0-4 and 7-11 to assess the use of the serum and urinary
biomarkers as indices of chemoprotective efficacy. In the rats fed
1,2-dithiole-3-thione, the overall diminutions in the levels of hepatic
DNA adducts, urinary aflatoxin-N7-guanine and serum
aflatoxin-
albumin adducts over the 2 week exposure period were 76, 62 and 66% respectively. This parallelism in reductions of levels of
biomarkers relative to target organ
DNA adduct burden suggests that these
biomarkers are predictive short-term, non-invasive measures for assessing the efficacy of chemoprotective interventions in experimental studies and can be applied to human clinical trials directed at populations at high risk for
aflatoxin exposure and primary
hepatocellular carcinoma.