What is diindolylmethane?

What is Diindolylmethane (DIM)?

Diindolylmethane (DIM) is a bioactive compound formed from the acid-catalyzed breakdown of indole-3-carbinol found in cruciferous vegetables (broccoli, cauliflower, cabbage, brussels sprouts), available as a dietary supplement typically dosed at 150 mg per capsule, with demonstrated chemopreventive activities in breast cancer through modulation of estrogen metabolism. 1, 2, 3

Chemical Origin and Formation

• DIM is synthesized after glycolysis from the glucosinolate structure in cruciferous vegetables, specifically through acid-catalyzed dimerization of indole-3-carbinol in the stomach 3
• The compound represents one of several bioactive chemicals produced when cruciferous vegetables are consumed and digested 1
• DIM has been documented to have chemopreventive activities in all stages of breast cancer carcinogenesis 1

Mechanism of Action

• DIM binds to receptors associated with sex steroid pathways and has effects on estrogen and androgen physiology 4
• The compound acts as a selective aryl hydrocarbon receptor modulator (SAhRM), binding to the aryl hydrocarbon receptor but exhibiting minimal CYP1A1 induction at therapeutic doses 5
• DIM inhibits estrogen-induced cancer cell growth through modulation of estrogen-dependent and estrogen-independent pathways 3, 5

Clinical Applications and Evidence

• Estrogen metabolism modulation: DIM increases the urinary 2/16α-hydroxyestrone ratio, a biomarker associated with reduced breast cancer risk 6
• Sex hormone-binding globulin (SHBG): Clinical trials demonstrate DIM increases serum SHBG levels (+25 nmol/L vs +1.1 nmol/L with placebo), which may reduce bioavailable estrogen 6
• Cancer prevention: Preclinical and clinical trials have evaluated DIM for cervical dysplasia, prostate cancer, and breast cancer prevention with promising results 3

Metabolism and Pharmacokinetics

• Contrary to earlier studies, recent research demonstrates DIM undergoes significant phase 1 and phase 2 metabolism in humans 7
• Monohydroxylated and dihydroxylated metabolites appear rapidly in plasma and urine, along with their sulfate and glucuronide conjugates 7
• One metabolite, 3-((1H-indole-3-yl)methyl)indolin-2-one, exhibits greater potency as an aryl hydrocarbon receptor agonist than parent DIM 7
• The compound can also serve as a urinary biomarker of glucobrassicin exposure and indole-3-carbinol uptake from Brassica vegetables 1

Critical Drug Interaction Warning

DIM significantly reduces plasma concentrations of tamoxifen metabolites (endoxifen, 4-OH tamoxifen, N-desmethyl-tamoxifen) when co-administered, which may attenuate tamoxifen's clinical benefit. 6

• This interaction occurs despite DIM's favorable effects on estrogen metabolism markers 6
• Patients taking tamoxifen should avoid DIM supplementation until further research clarifies whether the reduction in endoxifen levels compromises tamoxifen efficacy 6

Potential Safety Concerns

• A case report documents possible association between DIM supplementation and venous thromboembolism (deep venous thrombosis and bilateral pulmonary embolism) in a 65-year-old man taking one tablet daily for 3-4 months 4
• While this represents a single case with multiple confounding risk factors (tobacco use, prior PE history, elevated BMI, age), clinicians should question patients about DIM supplementation when evaluating venous thromboembolism 4
• In controlled trials, minimal adverse events were reported and did not differ from placebo, with >91% compliance over 12 months 6

Pharmacologic Limitations

• DIM faces challenges related to low solubility and poor bioavailability 3
• Commercial formulations like BioResponse DIM® incorporate BioPerine® (black pepper extract) to enhance absorption 2
• Standard supplement formulations contain 150 mg DIM per capsule, often combined with broccoli extract, calcium D-glucarate, and absorption enhancers 2

Dietary Context

• Cruciferous vegetable intake of approximately 57 g/day (achievable through 5 servings/day of vegetables) provides protective amounts of DIM and related compounds against breast cancer recurrence 1
• Concerns about goitrin from cruciferous vegetables interfering with thyroid function are not biologically plausible at conventional nutritional recommendations (≤50 g/day), and 150 g/day of cooked cruciferous vegetables for 4 weeks showed no effect on thyroid function 1