Ingredient review

Diindolylmethane (DIM)

Description

What is it?

3,3’-Diindolylmethane (DIM) is one of the major bioactive components found in cruciferous vegetables, such as broccoli, bok choy, Brussels sprouts, cabbage, cauliflower, kale, and radishes. (10)(16) The majority (60%) of DIM is derived from the unstable phytochemical indole-3-carbinol (I3C). (16) DIM may provide anti-cancerous benefits, possibly through a variety of mechanisms. For example, DIM may increase the metabolism of estrogen, generating metabolites with anti-estrogenic activity. (13)(16) It may also inhibit androgenic activity, increase the activity of signaling pathways involved in reducing cancer cell survival and proliferation, and improve apoptosis, angiogenesis, DNA repair, epigenetic modification, and inflammation. (7)(9) To date, most of the research has focused on the benefits of consuming cruciferous vegetables, but research on DIM supplementation is limited. (16) Though DIM is a metabolite of I3C, this review only details DIM supplementation trials and does not consider I3C. Evidence without control groups may indicate benefits from the use of DIM in prostate cancer via reductions in prostate-specific antigen (6) and in breast cancer via reductions in estradiol (46%), testosterone (26%), and breast density (5%). (17)

Main uses

Hormonal modulation

Formulations

Formulation
Characteristics
BioResponse-DIM® (BR-DIM)
(Patented formula) of microencapsulated DIM, containing starch, diindolylmethane, vitamin E (as tocophersolan), phosphatidylcholine, silica, available in various DIM products
BR-DIM increased relative bioavailability by 50% compared to standard crystalline DIM in rodents. (1)
Pure crystalline DIM
Relatively insoluble in water and oil, providing low bioavailability (16)

Dosing & administration

Adverse effects

Generally, DIM is considered to be well tolerated with few adverse effects. Nausea, vomiting, headaches, gastrointestinal distress, diarrhea, dizziness, hyperglycemia, hyponatremia, feelings of thirst, decreased appetite, and darkening of urine color have been reported but are either not compared to a control group or are self-resolving with continued use. (6)(8)(14) Furthermore, compared with placebo, there were no greater levels of reported side effects, (5) except for discolored urine, which was reported in about 40% of DIM supplemented users. (15)

Pharmacokinetics

Absorption

  • Rapidly absorbed with a max concentration occurring within two to four hours using BioResponse-DIM® (6)

Distribution

  • Primarily distributed to the liver, followed by the lung, kidneys, and heart, though smaller amounts can be found in plasma and the brain as shown in mice (1)(16)

Metabolism

  • DIM is produced by the condensation of I3C under acidic conditions of the stomach (10)(16)
  • DIM may induce phase I metabolism via CYP1A1, CYP1A2, CYP1B1, and CYP3A4 (9)(12)
  • DIM may induce phase II metabolism via glutathione-S-transferases and NAD(P)H:quinone oxidoreductases and drug transporters including multidrug resistance protein 1 (9)(12)

Excretion

  • Eliminated in the urine (2)(3)(4)
  • Half-life is between 2.6 to 4.5 hours (16)
  • May be almost completely eliminated within 12 hours (4)

References

  1. Anderton, M. J., Manson, M. M., Verschoyle, R., Gescher, A., Steward, W. P., Williams, M. L., & Mager, D. E. (2004). Physiological modeling of formulated and crystalline 3,3’-diindolylmethane pharmacokinetics following oral administration in mice. Drug Metabolism and Disposition, 32(6), 632–638. https://doi.org/10.1124/dmd.32.6.632 
  2. Dalessandri, K. M., Firestone, G. L., Fitch, M. D., Bradlow, H. L., & Bjeldanes, L. F. (2004). Pilot study: Effect of 3,3’-diindolylmethane supplements on urinary hormone metabolites in postmenopausal women with a history of early-stage breast cancer. Nutrition and Cancer, 50(2), 161–167. https://doi.org/10.1207/s15327914nc5002_5 
  3. Fujioka, N., Ainslie-Waldman, C. E., Upadhyaya, P., Carmella, S. G., Fritz, V. A., Rohwer, C., Fan, Y., Rauch, D., Le, C., Hatsukami, D. K., & Hecht, S. S. (2014). Urinary 3,3’-diindolylmethane: a biomarker of glucobrassicin exposure and indole-3-carbinol uptake in humans. Cancer Epidemiology, Biomarkers & Prevention:, 23(2), 282–287. https://doi.org/10.1158/1055-9965.EPI-13-0645 
  4. Fujioka, N., Ransom, B. W., Carmella, S. G., Upadhyaya, P., Lindgren, B. R., Roper-Batker, A., Hatsukami, D. K., Fritz, V. A., Rohwer, C., & Hecht, S. S. (2016). Harnessing the power of cruciferous vegetables: Developing a biomarker for brassica vegetable consumption using urinary 3,3’-diindolylmethane. Cancer Prevention Research, 9(10), 788–793. https://doi.org/10.1158/1940-6207.CAPR-16-0136 
  5. Gee, J. R., Saltzstein, D. R., Messing, E., Kim, K., Kolesar, J., Huang, W., Havighurst, T. C., Harris, L., Wollmer, B. W., Jarrard, D., House, M., Parnes, H., & Bailey, H. H. (2016). Phase Ib placebo-controlled, tissue biomarker trial of diindolylmethane (BR-DIMNG) in patients with prostate cancer who are undergoing prostatectomy. European Journal of Cancer Prevention, 25(4), 312–320. https://doi.org/10.1097/CEJ.0000000000000189 
  6. Heath, E. I., Heilbrun, L. K., Li, J., Vaishampayan, U., Harper, F., Pemberton, P., & Sarkar, F. H. (2010). A phase I dose-escalation study of oral BR-DIM (BioResponse 3,3’- Diindolylmethane) in castrate-resistant, non-metastatic prostate cancer. American Journal of Translational Research, 2(4), 402–411. https://www.ncbi.nlm.nih.gov/pubmed/20733950 
  7. Kim, S. M. (2016). Cellular and molecular mechanisms of 3,3’-diindolylmethane in gastrointestinal cancer. International Journal of Molecular Sciences, 17(7). https://doi.org/10.3390/ijms17071155 
  8. Kotsopoulos, J., Zhang, S., Akbari, M., Salmena, L., Llacuachaqui, M., Zeligs, M., Sun, P., & Narod, S. A. (2014). BRCA1 mRNA levels following a 4-6-week intervention with oral 3,3’-diindolylmethane. British Journal of Cancer, 111(7), 1269–1274. https://doi.org/10.1038/bjc.2014.391
  9. Licznerska, B., & Baer-Dubowska, W. (2016). Indole-3-carbinol and its role in chronic diseases. Advances in Experimental Medicine and Biology, 928, 131–154. https://doi.org/10.1007/978-3-319-41334-1_6
  10. Maruthanila, V. L., Poornima, J., & Mirunalini, S. (2014). Attenuation of carcinogenesis and the mechanism underlying by the influence of indole-3-carbinol and its metabolite 3,3’-diindolylmethane: A therapeutic marvel. Advances in Pharmacological Sciences, 2014, 832161. https://doi.org/10.1155/2014/832161 
  11. Morales-Prieto, D. M., Herrmann, J., Osterwald, H., Kochhar, P. S., Schleussner, E., Markert, U. R., & Oettel, M. (2018). Comparison of dienogest effects upon 3,3’-diindolylmethane supplementation in models of endometriosis and clinical cases. Reproductive Biology, 18(3), 252–258. https://doi.org/10.1016/j.repbio.2018.07.002 
  12. Pondugula, S. R., Flannery, P. C., Abbott, K. L., Coleman, E. S., Mani, S., Samuel, T., & Xie, W. (2015). Diindolylmethane, a naturally occurring compound, induces CYP3A4 and MDR1 gene expression by activating human PXR. Toxicology Letters, 232(3), 580–589. https://doi.org/10.1016/j.toxlet.2014.12.015 
  13. Rajoria, S., Suriano, R., Parmar, P. S., Wilson, Y. L., Megwalu, U., Moscatello, A., Bradlow, H. L., Sepkovic, D. W., Geliebter, J., Schantz, S. P., & Tiwari, R. K. (2011). 3,3’-diindolylmethane modulates estrogen metabolism in patients with thyroid proliferative disease: A pilot study. Thyroid: Official Journal of the American Thyroid Association, 21(3), 299–304. https://doi.org/10.1089/thy.2010.0245 
  14. Reed, G. A., Sunega, J. M., Sullivan, D. K., Gray, J. C., Mayo, M. S., Crowell, J. A., & Hurwitz, A. (2008). Single-dose pharmacokinetics and tolerability of absorption-enhanced 3,3’-diindolylmethane in healthy subjects. Cancer Epidemiology, Biomarkers & Prevention, 17(10), 2619–2624. https://doi.org/10.1158/1055-9965.EPI-08-0520 
  15. Thomson, C. A., Chow, H. H. S., Wertheim, B. C., Roe, D. J., Stopeck, A., Maskarinec, G., Altbach, M., Chalasani, P., Huang, C., Strom, M. B., Galons, J.-P., & Thompson, P. A. (2017). A randomized, placebo-controlled trial of diindolylmethane for breast cancer biomarker modulation in patients taking tamoxifen. Breast Cancer Research and Treatment, 165(1), 97–107. https://doi.org/10.1007/s10549-017-4292-7 
  16. Thomson, C. A., Ho, E., & Strom, M. B. (2016). Chemopreventive properties of 3,3’-diindolylmethane in breast cancer: Evidence from experimental and human studies. Nutrition Reviews, 74(7), 432–443. https://doi.org/10.1093/nutrit/nuw010 
  17. Yerushalmi, R., Bargil, S., Ber, Y., Ozlavo, R., Sivan, T., Rapson, Y., Pomerantz, A., Tsoref, D., Sharon, E., Caspi, O., Grubsrein, A., & Margel, D. (2020). 3,3-Diindolylmethane (DIM): A nutritional intervention and its impact on breast density in healthy BRCA carriers. A prospective clinical trial. Carcinogenesis, 41(10), 1395–1401. https://doi.org/10.1093/carcin/bgaa050