3,3'-Diindolylmethane
Diindolylmethane/Drug Interactions:
Anti-inflammatory agentsAnti-inflammatory agents: In mice, DIM demonstrated anti-inflammatory effects (21). Antidiabetic agentsAntidiabetic agents: According to human research, DIM may cause hyperglycemia (39). Antineoplastic agentsAntineoplastic agents: In human, animal, and laboratory research, DIM displayed anticancer effects for various cancers (4; 36; 21; 42; 43; 1; 44; 45; 46; 47; 48; 49; 50; 51; 52). DIM has been shown to enhance the effects of various antineoplastic agents (53). In vitro and in vivo, DIM potentiated erlotinib's apoptosis-inducing effects (54). In pancreatic cancer cells, the cytotoxic effects of gemcitabine increased upon pretreatment with DIM (52). In human prostate cancer cells in vitro, the inhibition of cancer cell growth by idarubicin was enhanced by DIM in a dose-dependent manner (55). In vitro, DIM enhanced the effects of paclitaxel on HER2/neu breast cancer cells (56). Combined use of docetaxel and DIM compounds has been found to act additively or synergistically (57; 58; 51; 50). In laboratory research, DIM enhanced docetaxel-induced growth inhibition of breast cancer cells through downregulation of forkhead box protein M1 (FoxM1) (57). DIM enhanced the efficacy of docetaxel in hormone-refractory prostate cancer cells through surviving downregulation and reduced nuclear factor-kappaB (NF-kappaB) DNA-binding activity (58). In lung cancer cells, combined use was associated with mitochondrial-driven apoptosis that involved activation of procaspase-3, procaspase-9, decreased expression of Bcl-xL, and increased expression of bax and cleaved poly(ADP-ribose) polymerase (PARP) in vitro (51). In a murine model for lung cancer, DIM-C-pPhC6H5 aerosol enhanced the anticancer activity of docetaxel (50). It has been determined that NF-kappaB activation plays a role in cisplatin resistant squamous cell carcinoma (SCC). In laboratory research, 3,3'-diindolylmethane (BioResponse BR-DIM, referred to as B-DIM) inactivated NF-kappaB, resulting in cell growth inhibition and apoptosis (59). It has been suggested that DIM may be an efficacious adjuvant in patients with cisplatin-resistant SCC. In laboratory research, combined use of DIM, erlotinib, and gemcitabine led to greater antitumor activity in pancreatic cancer and greater inhibition of NF-kappaB, cyclooxygenase-2, and epidermal growth factor receptor (60). In laboratory research, I3C with flutamide was more effective than either agent alone in inhibiting the growth of prostate cancer cells (61) In animal research, DIM and I3C have been found to induce a number of CYP isoforms and alter the efficacy of chemotherapeutic agents like tamoxifen (62; 63). In rats I3C and DIM inhibited flavin-containing monooxygenase (FMO), thereby inhibiting tamoxifen N-oxide formation (62). Additionally, in animal research, I3C protected against the hepatotoxic effects of trabectedin (64). Although I3 C and DIM may act synergistically with chemotherapeutic agents, some studies caution that I3C may increase the formation of estrogen metabolites or activate estrogen receptors, which may stimulate the growth of cancer cells; however, further research is needed (11; 12; 13). AntiparasiticsAntiparasitics: In laboratory research, DIM demonstrated antiparasitic effects against Leishmania species (65; 66). Cytochrome P450metabolized agentsCytochrome P450-metabolized agents: According to laboratory and animal research, DIM and I3C may induce mixed function oxidase activity in microsomes (67; 68). In animal and laboratory research, DIM and I3C have been found to induce various CYP isoforms, including CYP1A1 (strong) (62; 69; 70; 71; 3; 72; 63; 73; 74; 11; 75; 76; 7; 77; 78; 79), CYP1A2 (modest) (62; 46; 70; 71; 73; 74; 76; 77; 78; 79), CYP2B1/2 (modest) (62; 3; 73; 74; 76; 77), and CYP3A (modest to weak) (62; 74; 76; 77; 79; 71). In rodents and trout, DIM has been found to strongly inhibit CYP1A1, 1A2, and 2B1 (16). Drugs that affect electrolyte levelsDrugs that affect electrolyte levels: In clinical research, DIM 300mg reportedly caused hyponatremia in two patients, but the patients were asymptomatic (39). EstrogensEstrogens: According to a review and animal studies, I3C and DIM induce the enzymes that are responsible for phase I and phase II metabolism, leading to estrogen detoxification (12; 63). In laboratory research, DIM has also been found to be an activator of the estrogen receptor that requires protein kinase A-dependent phosphorylation of cAMP response element-binding protein (CREB) (80). The combination of estradiol (E2) and DIM on MCF7 (a breast cancer cell line) was antagonistic (81). In laboratory research, the combined treatment of E2 and DIM altered gene expression and resulted in an increased expression of CYP1A1, CYP1B1, PGDH, AS, P8, Caldesmon, and SCD, and decreased expression of CXCR4, TGFb-1, and BCLL-6 (81). HyperglycemicsHyperglycemics: According to human research, DIM may cause hyperglycemia (39). ImmunosuppressantsImmunosuppressants: According to in vitro and in vivo research, DIM was found to have immune-stimulating effects and directly affect splenocyte and macrophage function (82). In laboratory research, DIM stimulated the production of cytokines, including granulocyte colony-stimulating factor (G-CSF), interleukin-6 (IL-6), interleukin-12 (IL-12), and interferon (IFN)-gamma (82). InterferonsInterferons: In breast cancer cells, concurrent use of DIM and interferon-gamma resulted in additive inhibition of cell proliferation and a synergistic increase in levels of major histocompatibility complex class-1 (MHC-1) expression and mRNAs of MHC-1-associated proteins and transporters (48). LaxativesLaxatives: According to human research, DIM may cause diarrhea (39). NicotineNicotine: In rats given nicotine with either DIM or I3C, there was a decreased ratio of flavin-containing monooxygenase (FMO) metabolites to CYP metabolites due to a reduction in FMO-mediated N-oxygenation (62). Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) modulatorsPeroxisome proliferator-activated receptor-gamma (PPAR-gamma) modulators: According to laboratory research, 1,1-bis(3'-indolyl)-1-(p-trifluoromethylphenyl)methane (DIM-C-pPhCF3) inhibited tumor growth through activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) (83; 84; 85). Protein kinase A (PKA) modulatorsProtein kinase A (PKA) modulators: In human breast cancer (MCF-7) cells, the effects of DIM were blocked by cotreatment with the PKA inhibitor H-89 (N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide) (86). Diindolylmethane /Herb/Supplement Interactions:
Anti-inflammatory herbsAnti-inflammatory herbs: In mice, DIM demonstrated anti-inflammatory effects (21). AntineoplasticsAntineoplastics: In human, animal, and laboratory research, DIM displayed anticancer effects for various cancers (4; 36; 21; 42; 43; 1; 44; 45; 46; 47; 48; 49; 50). DIM induced apoptosis in prostate cancer cells and inhibited cell viability and growth (52). DIM has been shown to enhance the effects of various antineoplastic agents (54; 52; 55; 56; 59; 62; 63; 50; 51; 53; 58; 61). Additionally, in animal research, I3C was found to protect against chemotherapy-related toxicity, specifically hepatotoxicity caused by trabectedin (64). Although I3C and DIM may act synergistically with chemotherapeutic agents, some studies caution that I3C may increase the formation of estrogen metabolites or activate estrogen receptors, which may stimulate the growth of cancer cells; however, further research is needed (11; 12; 13). AntioxidantsAntioxidants: In vitro, I3C and DIM demonstrated radical-scavenging activity (87; 88). In laboratory research, DIM protected against oxidative stress, as evidenced by decreased vascular cell adhesion molecule-1 (VCAM-1) and leukocyte recruitment of breast cancer susceptibility gene-1 (BRCA1) expression, in a dose-dependent manner (89; 90). AntiparasiticsAntiparasitics: In laboratory research, DIM demonstrated antiparasitic effects against Leishmania species (65; 66). Cytochrome P450-metabolized herbs and supplementsCytochrome P450-metabolized herbs and supplements: According to laboratory and animal research, DIM and I3C may induce mixed-function oxidase activity in microsomes (67; 68). In animal and laboratory research, DIM and I3C have been found to induce various CYP isoforms, including CYP1A1 (strong) (62; 69; 70; 71; 3; 72; 63; 73; 74; 11; 75; 76; 7; 77; 78; 79), CYP1A2 (modest) (62; 46; 70; 71; 73; 74; 76; 77; 78; 79), CYP2B1/2 (modest) (62; 3; 73; 74; 76; 77), and CYP3A (modest to weak) (62; 74; 76; 77; 79; 71). In rodents and trout, DIM was found to strongly inhibit CYP1A1, 1A2, and 2B1 (16). Fat-soluble vitaminsFat-soluble vitamins: According to secondary sources, DIM is a lipophilic compound. Vitamin E may increase the absorption and bioavailability of DIM.GenisteinGenistein: According to laboratory research, concurrent use of genistein and DIM or I3C may have synergistic effects (91). In vitro, genistein and DIM together increased apoptosis (91) and lowered CXCR4 and CXCL12 levels more than either component alone (92). Herbs and supplements that affect electrolyte levelsHerbs and supplements that affect electrolyte levels: In clinical research, DIM 300mg reportedly caused hyponatremia in two patients, but the patients were asymptomatic (39). HyperglycemicsHyperglycemics: According to human research, DIM may cause hyperglycemia (39). HypoglycemicsHypoglycemics: According to human research, DIM may cause hyperglycemia (39). ImmunosuppressantsImmunosuppressants: In in vitro and in vivo research, DIM was found to have immune-stimulating effects and directly affect splenocyte and macrophage function (82). In laboratory research, DIM stimulated the production of cytokines, including granulocyte colony-stimulating factor (G-CSF), interleukin-6 (IL-6), interleukin-12 (IL-12), and interferon (IFN)-gamma (82) Indole [3,2-b]carbazole (ICZ)Indole [3,2-b]carbazole (ICZ): In vitro, ICZ increased the oxidation of DIM in MCF-7 breast cancer cells (93). InositolInositol: In animal research, combined use of I3C or DIM with myo-inositol reduced the multiplicity of smoke carcinogen-induced lung tumors in mice more effectively than the individual compounds alone (94). The combination also reduced the activation of Akt extracellular signal-regulated kinase and nuclear factor-kappaB in lung tumor tissues. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) modulatorsPeroxisome proliferator-activated receptor-gamma (PPAR-gamma) modulators: According to laboratory research, 1,1-bis(3'-indolyl)-1-(p-trifluoromethylphenyl)methane (DIM-C-pPhCF3) inhibited tumor growth through activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) (83; 84; 85). PhosphatidylcholinePhosphatidylcholine: According to secondary sources, DIM is a lipophilic compound. Phosphatidylcholine may increase the absorption and bioavailability of DIM.PhytoestrogensPhytoestrogens: According to a review and animal studies, I3C and DIM induce the enzymes that are responsible for phase I and phase II metabolism, leading to estrogen detoxification (12; 63). In laboratory research, DIM has also been found to be an activator of the estrogen receptor that requires protein kinase A-dependent phosphorylation of cAMP response element-binding protein (CREB) (80). The combination of estradiol (E2) and DIM on MCF7 (a breast cancer cell line) was antagonistic (81). In laboratory research, the combined treatment of E2 and DIM altered gene expression, resulting in an increased expression of CYP1A1, CYP1B1, PGDH, AS, P8, Caldesmon, and SCD, and decreased expression in CXCR4, TGFb-1, and BCLL-6 (81). Protein kinase A (PKA) modulatorsProtein kinase A (PKA) modulators: In human breast cancer (MCF-7) cells, the effects of DIM were blocked by cotreatment with the PKA inhibitor H-89 (N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide) (86). QuercetinQuercetin: In vitro, quercetin slowed the oxidation of DIM in MCF-7 breast cancer cells (46). TobaccoTobacco: In rats given nicotine with either 3,3'-diindolylmethane (DIM) or its parent compound, indole-3-carbinol (I3C), there was a decreased ratio of flavin-containing monooxygenase (FMO) metabolites to CYP metabolites, due to a reduction in FMO-mediated N-oxygenation (62). Diindolylmethane/Food Interactions:
Foods containing fat-soluble vitaminsFoods containing fat-soluble vitamins: According to secondary sources, DIM is a lipophilic compound. Vitamin E may increase the absorption and bioavailability of DIM.SoySoy: According to laboratory research, concurrent use of genistein, a constituent of soy, and DIM or I3C may have synergistic effects (91). In vitro, genistein and DIM together increased apoptosis (91) and lowered CXCR4 and CXCL12 levels more than either component alone (92). Diindolylmethane/Lab Interactions:
Blood glucoseBlood glucose: According to human research, DIM may cause hyperglycemia (39). ColposcopyColposcopy: In clinical trial of women with cervical intraepithelial neoplasia, DIM improved colposcopy results with a decrease in involved quadrants and with a decrease in lesion number (36). CortisollevelsCortisollevels: In clinical research in postmenopausal women with early-stage breast cancer, 108mg of DIM daily for 30 days was found to increase cortisol levels (4). Creatine kinase (CK)Creatine kinase (CK): According to toxicity studies conducted in rats, dietary DIM may cause general decreases in creatine kinase (CK), which may be associated with protective effects (40). Diindolylmethane levelsDiindolylmethane levels: In clinical research in postmenopausal women with early-stage breast cancer, 108mg of DIM daily for 30 days increased levels of DIM (4). Estrogen metabolites (urinary)Estrogen metabolites (urinary): In clinical research in postmenopausal women with early-stage breast cancer, 108mg of diindolylmethane daily for 30 days increased levels of 2-OHE1 and the 2-OHE1:16alpha-OHE1 ratio (4). Hypoxia-inducible factor (HIF)-1alpha: Hypoxia-inducible factor (HIF)-1alpha: In vitro, DIM decreased levels and inhibited transcriptional activity of hypoxia-inducible factor (HIF)-1alpha, a key angiogenesis regulatory factor (95). Liver function testsLiver function tests: According to toxicity studies conducted in rats, dietary DIM may cause general decreases in hepatic enzymes, including aspartate aminotransferase [AST], alanine aminotransferase [ALT], and alkaline phosphatase [ALP]), which has been associated with protective effect (40). Pap smearPap smear: In human research, oral DIM resulted in improved results of the Pap smear (36). Prostate-specific antigen (PSA)Prostate-specific antigen (PSA): In clinical research in patients with castrate-resistant, nonmetastatic prostate cancer, one patient experienced a decline in prostate-specific antigen (PSA) by 50%, another patient experienced PSA stabilization, and the other patients experienced a decrease in their slope of PSA rise but then returned to progression or metastasized after DIM treatment (39). SodiumSodium: In clinical research, DIM 300mg reportedly caused hyponatremia in two patients, but the patients were asymptomatic (39).