Indole-3-carbinol (I3C) is a naturally occurring plant alkaloid, found in
significant concentrations in cruciferous vegetables such as broccoli and Brussels
sprouts. I3C is an unstable compound that undergoes rapid oligomerization in an
acidic environment to form higher order condensation products (I3C-ACPs), such
as 3-3'-diindolylmethane (DIM). Both I3C and DIM are marketed as dietary
supplements and are under investigation as potential chemopreventive agents,
despite limited data on the effects of chronic exposure. Previous studies have
demonstrated that the chemopreventive potential of I3C and DIM in animal studies
is dependent on species, strain, tissue and timing of treatment relative to carcinogen
exposure, and long-term post-initiation exposure can even promote tumors. The
majority of biological effects from I3C are the result of the abilities DIM and other
I3C-ACPs to bind to the aryl hydrocarbon receptor and the subsequent induction of
phase I and phase II enzymes. Phase I and phase II enzyme induction in many
cases leads to protection from carcinogens by increasing the rate of metabolism and
excretion but in some cases enhances carcinogenicity by increasing the rate of
bioactivation. It has been demonstrated that modulation of enzyme levels can also
result in altered metabolism of compounds that could affect efficacy and toxicity of
pharmaceuticals and xenobiotics. The current work utilizes chronic dietary I3C and
DIM exposures in rodent models to further elucidate the effect these compounds
might have on health, drug metabolism and carcinogenesis. The reduced weight of
Fischer 344 rats treated with 2500 ppm I3C for 1 year may be indicative of adverse
effects but toxicity was not confirmed by blood chemistry or histopathological
examination. Furthermore, no toxicity was observed after a comparable treatment
of Sprague-Dawley rats. As observed after acute and sub-chronic exposures to I3C
and DIM, we documented significant induction of cytochrome P450 enzymes and a
related modification to drug metabolism in liver slice incubations. Evidence is also
provided that may suggest that tumor modulation in mice may occur through an
estrogenic mechanism. Further studies should be completed to determine the
potential for similar responses in humans. / Graduation date: 2004
| Identifer | oai:union.ndltd.org:ORGSU/oai:ir.library.oregonstate.edu:1957/31050 |
| Date | 10 September 2003 |
| Creators | Leibelt, Dustin A. |
| Contributors | Williams, David E. |
| Source Sets | Oregon State University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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