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Promotion of Aflatoxin B₁ Carcinogenesis by the Natural Tumor Modulator Indole-3-carbinol: Influence of Dose, Duration, and Intermittent Exposure on Indole-3-carbinol Promotional Potency¹

Department of Environmental Biochemistry, University of Hawaii, Honolulu, Hawaii 96822 [R. H. D.], and Department of Food Science and Technology, Oregon State University, Corvallis, Oregon 97331 [A. T. F., D. E. W., J. D. H., G. S. B.]

Indole-3-carbinol (I3C), a secondary metabolite from cruciferous vegetables, inhibits aflatoxin B₁ (AFB₁) hepatocarcinogenesis in trout (Bailey et al., J. Natl. Cancer Inst., 78: 931–934, 1987) and rats (Selivonchick et al., unpublished results) when given prior to and with carcinogen but promotes carcinogenesis in both species when given continuously following AFB₁ initiation. Since human I3C intake may not be continuous, and the promotional stimulation may be reversible, we have assessed I3C promotion using delayed and discontinuous exposure protocols. Following initiation with AFB₁, I3C was fed to trout for varying periods of time, with varying lengths of delay after initiation and continuous or intermittent patterns of I3C treatment. Promotional enhancement of tumor incidence by I3C was found to be significant when I3C treatment was delayed for several weeks or months after the initial AFB₁ challenge. Promotion also was found to increase with length of exposure to I3C treatment and to be decreased but still evident when I3C was given in alternating months or weeks, or twice per week only. These results do not support the idea that promotional stimulation in hepatocarcinogenesis is a reversible phenomenon.

To quantify I3C promotional potency in terms of its dietary concentration, a series of AFB₁ tumor dose-response curves was established, each with a different level of I3C fed continuously following AFB₁ initiation. The resultant tumor dose-response curves, plotted as logit percentage of incidence versus log AFB₁ dose, were displaced parallel toward lower AFB₁ 50% tumor take (TD₅₀) values with increasing I3C concentration. The level of I3C that halves the AFB₁ dose for 50% tumor incidence was calculated to be approximately 1000 ppm I3C, fed continuously, with no substantial threshold for promotion. By comparison, I3C, when fed before and with AFB₁, shows a 50% inhibitory value (I3C concentration that doubles the dose of AFB₁ for 50% tumor incidence) in trout of 1400 ppm I3C [Dashwood et al., Carcinogenesis (Lond.), 10: 175–181, 1989]. Thus the potential for I3C as a dietary additive to promote prior hepatic initiation events when fed continuously is approximately as great as its potential to inhibit concurrent AFB₁ initiation.

¹ This work was supported by USPHS Grants CA34742, EH03850, and EH00210. This is Technical Paper 9530 of the Oregon Agricultural Experiment Station.

² To whom requests for reprints should be addressed, at Department of Environmental Biochemistry, University of Hawaii at Manoa, Henke Hall 329, 1800 East-West Road, Honolulu, HI 96822.

Received 10/15/90. Accepted 2/15/91.

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