Development of a multi-organ rat model for evaluating chemopreventive agents: efficacy of indole-3-carbinol

Gary Stoner1,5, Bruce Casto1, Sherry Ralston1, Bill Roebuck2, Clifford Pereira3 and George Bailey4

1 Division of Environmental Health Sciences, School of Public Health, College of Medicine and Public Health, The Ohio State University, Columbus, OH,
2 Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH,
3 Statistics Department, Oregon State University, Corvallis, OR and
4 Medical Biochemistry Department MFBS Center, Oregon State University, Corvallis, OR, USA

We appreciate the comments of Johnson and Huff. They focus their initial remarks on ‘Janus’ compounds that are carcinogenic. We wish to stress however, that there is no evidence that I3C is a complete carcinogen in any animal model. In that sense, I3C could be regarded as a potentially safer alternative to tamoxifen for intervention studies in high-risk patients. However, we have known for 15 years that I3C given post-initiation displays potent liver tumor promotional activity in the rainbow trout (1), which increases with dose and duration of exposure (2). The recent studies now extend this finding to the rat (3,4). Though I3C is often regarded as a natural anti-estrogen, there was ample evidence that this compound given orally can also elicit estrogenic responses in vivo, for instance in inducing estrogen-responsive genes in the trout (5) and in mimicking the ability of estradiol to suppress liver carcinogenesis in the mouse (6). It is this kind of dualistic activity, which Johnson and Huff so aptly term ‘Janus’ behavior, that raises our concern, especially for the general public consuming high doses of I3C as an ‘anti-estrogen’ supplement. Current data does not support the clinical assumption that long-term I3C administration will have negligible risk. As a consequence, we believe it prudent at this time to restrict long-term clinical use of I3C to fully informed, high-risk individuals, for whom the potential therapeutic benefits may be judged to outweigh its potential risks in promoting liver cancer.

Notes

5 To whom correspondence should be addressed Email: stoner.21{at}osu.edu Back

References

  1. Bailey,G.S., Hendricks,J.D., Shelton,D.W., Nixon,J.E. and Pawlowski,N.E. (1987) Enhancement of carcinogenesis by the natural anticarcinogen indole-3-carbinol. J. Natl. Cancer Inst., 78, 931–934.[ISI][Medline]
  2. Dashwood,R.H., Fong,A.T., Williams,D.E., Hendricks,J.D. and Bailey,G.S. (1991) 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 potency. Cancer Res., 51, 2362–2365.[Abstract]
  3. Kim,D.J., Han,B.S., Ahn,B., Hasegawa,R., Shirai,T., Ito,N. and Tsuda,H. (1997) Enhancement by indole-3-carbinol of liver and thyroid gland neoplastic development in a rat medium-term multiorgan carcinogenesis model. Carcinogenesis, 18, 377–381.[Abstract]
  4. Stoner,G., Casto,B., Ralston,S., Roebuck,B., Pereira,C. and Bailey,G. (2002) Development of a multi-organ rat model for evaluating chemopreventive agents: efficacy of indole-3-carbinol. Carcinogenesis, 23, 265–272.[Abstract/Free Full Text]
  5. Shilling,A.D., Carlson,D.B., Katchamart,S. and Williams,D.E. (2001) 3,3'-Diindolylmethane, a Major Condensation Product of Indole-3-carbinol, Is a Potent Estrogen in the Rainbow Trout. Toxicol. Appl. Pharmacol., 170, 191–200.[ISI][Medline]
  6. Oganasian,A., Hendricks,J.D. and Williams,D.E. (1997) Long term dietary indole-3-carbinol inhibits diethylnitrosamine-initiated hepatocarcinogenesis in the infant mouse model. Cancer Lett., 118, 87–94.[ISI][Medline]
Received July 3, 2002; accepted July 3, 2002.





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