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ToxSci Advance Access published online on May 2, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg103
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received January 20, 2003; accepted March 26, 2003
© 2003 Society of Toxicology

Biotransformation and Toxicokinetics

Evaluation of Chronic Dietary Exposure to Indole-3-Carbinol and Absorption-Enhanced 3,3'-Diindolylmethane in Sprague-Dawley Rats

Dustin A. Leibelt 1, Olaf R. Hedstrom 2, Kay A. Fischer 2, Clifford B. Pereira 3, David E. Williams 1*

1 Department of Environmental and Molecular Toxicology and the Linus Pauling Institute, Oregon State University, Corvallis, Oregon 97331
2 College of Veterinary Medicine, Oregon State University, Corvallis, Oregon 97331
3 Statistics Department, Oregon State University, Corvallis, Oregon 97331

* To whom correspondence should be addressed. E-mail: david.williams{at}orst.edu.


  Abstract

Indole-3-carbinol (I3C) and 3,3'-diindolylmethane (DIM) are naturally occurring dietary components found in cruciferous vegetables. In the stomach, I3C forms condensation products including DIM. I3C and DIM are marketed as dietary supplements, but little is known about the safety of long-term exposure. Rats were fed either control diet, 1- or 10-X the current human dose of absorption-enhanced DIM or 5-7-X the maximal recommended dose of I3C. Experimental diets were fed continuously for 3 or 12 months or 2 months followed by control diet for 1 month. Results at 3 or 12 months were similar in most respects. No significant differences between groups were found in blood chemistry. A general decrease in serum enzyme levels in male rats was observed, perhaps indicative of a protective effect. Males fed I3C exhibited higher serum levels of 25-hydroxy-vitamin D3 (25OH-D3). There were no observable differences grossly or histologically between groups, although a high number of hyaline casts were found throughout the kidneys of all animals. In both sexes total hepatic CYP levels were significantly induced by I3C, but not by either dose of DIM. Induction of CYP1A1 and CYP1A2 in liver and CYP1A1 in colon was detected for both sexes fed I3C and the high dose of DIM. CYP3A2 was induced in females fed I3C or the high dose of DIM; males were induced with I3C, but not DIM. No induction of CYP1B1 in the colon was observed in either sex. Long-term exposure to DIM produced no observable toxicity and comparison to I3C indicates that DIM is a markedly less efficacious inducer of CYP in the rat at doses relevant to human supplementation.

Key Words: Indole-3-carbinol, 3,3-diindolylmethane, CYP1A1/1A2, CYP 3A2, bone density, 25-OH vitamin D3, clinical chemistry, histopathology, rat .


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