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Transient Intervention with Oltipraz Protects against Aflatoxin-induced Hepatic Tumorigenesis¹

Department of Environmental Health Sciences [M. G. B., J. D. G., T. W. K.] and Department of Epidemiology [A. M., L. P. J.], Johns Hopkins School of Hygiene and Public Health, Baltimore, Maryland 21205, and Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755 [Y. Y. M., B. D. R.]

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 dally with 25 µg 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-transferases 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 (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.

¹ This work was supported by Grants CA39416 and ES06052 from the NIH and by NIEHS Center Grant ES03819. J. D. G. is the recipient of NIH Research Career Development Award CA01517.

² To whom requests for reprints should be addressed, at Department of Environmental Health Sciences, Johns Hopkins School of Hygiene and Public Health, 615 N. Wolfe St., Baltimore, MD 21205.

Received 2/ 8/93. Accepted 5/20/93.

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