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Modulation of mycotoxin and nitrosamine carcinogenesis by indole-3-carbinol: quantitative analysis of inhibition
G S Bailey1, R H Dashwood, A T Fong
1Department of Food Science and Technology, Oregon State University, Corvallis.
Abstract:
The value of chemopreventive agents for reducing human response to mycotoxins and N-nitrosamines remains uncertain, especially since many such agents also can act as tumour promoters. Indole-3-carbinol (I3C) from cruciferous vegetables can inhibit DNA adduction and hepatocarcinogenesis induced by aflatoxin B1 (AFB1) or N-nitroso-diethylamine in trout if given before and with the carcinogen but promotes carcinogenesis when given after initiation. Similar results have been obtained with I3C and AFB1 in rats. In detailed studies using 10,000 trout, inhibition of AFB1 carcinogenesis was found to be saturable at high doses of I3C, approximately proportional to dose of I3C through the range of human intake and, within this range, quantitatively predicted by I3C-mediated reduction of AFB1-DNA adduction in liver. In a second study, post-initiation promotion of AFB1 carcinogenesis was approximately proportional to I3C dose, increased with duration of exposure, decreased with delayed onset of exposure, and reduced but still significant when I3C was given on alternate months or weeks or twice per week only. Hence, promotion by this common component of cruciferous vegetables required prolonged exposure but not necessarily on a daily basis.
Insights
Indole-3-carbinol (I3C) from cruciferous vegetables can prevent cancer initiation by aflatoxin B1 (AFB1) but promote it after initiation. Prolonged I3C exposure, not necessarily daily, is required for this promotion effect.
Area of Science:
- Biochemistry
- Toxicology
- Carcinogenesis
Background:
- Chemopreventive agents' efficacy against mycotoxins and N-nitrosamines is uncertain.
- Indole-3-carbinol (I3C), found in cruciferous vegetables, exhibits dual effects as a potential carcinogen inhibitor and promoter.
- Previous studies indicate I3C's context-dependent role in carcinogenesis.
Purpose of the Study:
- To investigate the dose-response and timing of Indole-3-carbinol (I3C) in modulating aflatoxin B1 (AFB1)-induced carcinogenesis.
- To determine the conditions under which I3C inhibits or promotes tumor development.
- To assess the relationship between I3C's chemopreventive effects and its impact on DNA adduction.
Main Methods:
- Utilized large-scale trout studies (n=10,000) and rat models to examine I3C's effects on AFB1-induced hepatocarcinogenesis.
- Administered I3C at various doses and timings relative to AFB1 exposure (before, during, and after initiation).
- Quantified AFB1-DNA adduction in the liver to correlate with carcinogenic outcomes.
Main Results:
- I3C inhibited AFB1-induced carcinogenesis in trout when administered before and with AFB1, with inhibition saturable at high doses.
- Post-initiation promotion of carcinogenesis by I3C was dose-dependent, increased with exposure duration, and decreased with delayed or intermittent exposure.
- I3C's inhibitory effect was proportional to dose within the human intake range and linked to reduced AFB1-DNA adduction.
Conclusions:
- I3C's chemopreventive activity against AFB1 is dose-dependent and linked to reduced DNA adduction.
- Promotion of carcinogenesis by I3C requires prolonged exposure, but not necessarily daily administration.
- Dietary I3C from cruciferous vegetables may have complex effects on cancer risk, influenced by timing and duration of intake.