Transient intervention with oltipraz protects against aflatoxin-induced hepatic tumorigenesis.
Oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione] protects against aflatoxin B1-induced hepatocarcinogenesis in rats when fed before and during carcinogen exposure; however, such an exposure-chemoprotection intervention paradigm is not directly relevant to most human populations. To model and assess the possible efficacy of short term interventions targeted at individuals at risk for sustained exposure to aflatoxins, 175-g male F344 rats were treated daily with 25 micrograms of aflatoxin B1, p.o., for 28 days. One week after the start of aflatoxin B1 exposure, half of the animals were fed a diet supplemented with 0.075% oltipraz for 10 days; these rats were then restored to the unsupplemented AIN-76A diet for the remainder of the experimental period. Livers were analyzed 2 or 3 months after the last aflatoxin B1 dose for burden of glutathione S-transferase P (GST-P)-positive foci, as an index of presumptive preneoplastic tumors. The transient intervention with oltipraz reduced the volume percent of hepatic GST-P-positive foci by 54% (P = 0.047) and 72% (P = 0.004) at 2 and 3 months, respectively. A strong positive correlation was also observed between the extent of fibrosis in the livers of these animals and the hepatic burden of GST-P-positive foci, implying that cytotoxicity is associated with the tumorigenic process. This protection may reflect alterations in the metabolism and disposition of aflatoxin B1 induced by oltipraz. Glutathione S-transferase catalyze the detoxication of aflatoxin-8,9-oxide and were found to be rapidly induced in the livers of animals after the beginning of the oltipraz intervention. Glutathione S-transferase activity remained significantly (P < 0.05) higher until 9 days after the end of the oltipraz intervention. In contrast, levels of hepatic aflatoxin-DNA adducts were not significantly reduced until 4 days after the beginning of the intervention but remained significantly (P < 0.05) lower up to 11 days after the end of the intervention. The cumulative reduction in levels of hepatic aflatoxin-DNA adducts (approximately 25%) by the oltipraz intervention underestimated the reduction in the hepatic burden of GST-P-positive foci. The significant protection against presumptive preneoplastic tumors, despite the delay of intervention, suggests that oltipraz may exert substantial activity against the cytotoxic and autopromoting action of repeated exposures to aflatoxin B1 and supports the utility of intervention trials with oltipraz in individuals chronically consuming aflatoxin B1-contaminated foods, particularly in regions with high incidences of liver cancer.
Bolton
M G
MG
Department of Environmental Health Sciences, Johns Hopkins School of Hygiene and Public Health, Baltimore, Maryland 21205.
Muñoz
A
A
Jacobson
L P
LP
Groopman
J D
JD
Maxuitenko
Y Y
YY
Roebuck
B D
BD
Kensler
T W
TW
D016604:Aflatoxin B1 / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D018736:DNA Adducts; D005982:Glutathione Transferase / Q000032:analysis / Q000037:antagonists & inhibitors; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D013871:Thiones; D013876:Thiophenes
D016588:Anticarcinogenic Agents; D018736:DNA Adducts; D011719:Pyrazines; D013871:Thiones; D013876:Thiophenes; C072611:aflatoxin B1-DNA adduct; C026209:oltipraz; D004247:DNA; D016604:Aflatoxin B1; D005982:Glutathione Transferase