Molecular dosimetry of urinary aflatoxin-N7-guanine and serum aflatoxin-albumin adducts predicts chemoprotection by 1,2-dithiole-3-thione in rats.
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.
Groopman
J D
JD
Department of Environmental Health Sciences, Johns Hopkins University, School of Hygiene and Public Health, Baltimore, MD 21205.
DeMatos
P
P
Egner
P A
PA
Love-Hunt
A
A
Kensler
T W
TW
D016604:Aflatoxin B1 / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000633:toxicity / Q000652:urine; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015415:Biomarkers; D004247:DNA / Q000378:metabolism*; D006147:Guanine / Q000031:analogs & derivatives* / Q000652:urine; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D011485:Protein Binding; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D012709:Serum Albumin / Q000378:metabolism*; D013871:Thiones / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*
D000970:Antineoplastic Agents; D015415:Biomarkers; D011719:Pyrazines; D012709:Serum Albumin; D013871:Thiones; D013876:Thiophenes; D006147:Guanine; C028319:2,3-dihydro-2-(N(7)-guanyl)-3-hydroxyaflatoxin B1; C026209:oltipraz; D004247:DNA; D016604:Aflatoxin B1; C049325:1,2-dithiol-3-thione