3,3′-Diindolylmethane Exhibits Significant Metabolism after Oral Dosing in Humans

Maier, Monica; Siddens, Lisbeth K.; Uesugi, Sandra L.; Choi, Jaewoo; Leonard, Scott W.; Pennington, Jamie; Tilton, Susan C.; Smith, Jordan N.; Ho, Emily; Chow, H.‐H. Sherry; Nguyen, Bach Mai Dolly; Kolluri, Siva Kumar; Williams, David E.

doi:10.1124/dmd.120.000346

Cited by 18 publications

(7 citation statements)

References 58 publications

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“…Incubations of DIM with liver microsomes from female rats fed diets containing β-naphthoflavone (BNF), phenobarbital (PB) or I3C, produced two unidentified mono-hydroxylated metabolites (112). Human MCF-7 breast cancer cells incubated with 1 µM with clinically demonstrated enhanced absorption, we found extensive and rapid appearance of metabolites in both plasma (Figure 2) and urine (Figure 3) (20). The profile of these metabolites was very similar to what Staub et al, (43) observed in vitro with MCF-7 cells (43).…”

Section: Pharmacokinetics Of Dim In Rodents and Humansmentioning

confidence: 92%

“…In MCF-7 cells the major mono-hydroxylated metabolite of DIM, 2-ox-DIM, failed to demonstrate any estrogenic activity. When we examined this same metabolite in an AHR reporter system we found it to be a more potent agonist than parent DIM and as potent or more so than known indole AHR agonists derived from microbial or host metabolism of tryptophan (i.e., indole-3-acetonitrile, kynurenine, indole, indole-3-aldehyde and indole-3-acetate) (20,120). There is a possibility that metabolites of DIM may contribute to its beneficial chemopreventive properties.…”

Section: Pharmacokinetics Of Dim In Rodents and Humansmentioning

confidence: 97%

“…Unlike their study, the major site of hydroxylation in our in vivo study was not the 2-position but rather the 3-methylene position of DIM. Both of these mono-hydroxylated DIM metabolites were rapidly conjugated and sulfation seem to predominant (as in MCF-7 cells) although glucuronides were also present (Figure 2) (20). No di-sulfate, di-glucuronide or sulfate-glucuronide conjugates were found in plasma or in urine.…”

Section: Pharmacokinetics Of Dim In Rodents and Humansmentioning

confidence: 97%

“…A reasonable presumption is that a portion, if not the majority, of the cellular effects reported following incubation with I3C, especially with long incubations at concentrations typically ≥100 µM, are due to DIM rather than I3C. The relevance of many in vitro studies of DIM (typically at concentrations of 10-100 µM) in cancer cells could also be questioned as plasma levels following ingestion of supplements have been reported to be ≤1 µM and recent evidence in humans show that a significant portion exists as DIM metabolites with unknown pharmacological activity (20). I3C/DIM impacts cancer cells in numerous ways including inhibition of proliferation, stimulation of apoptosis and alteration of cell cycle control (9,(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33).…”

Section: In Vitro Studiesmentioning

confidence: 99%

“…The relevance of many in vitro studies of DIM (typically at concentrations of 10-100 µM) in cancer cells could also be questioned as plasma levels following ingestion of supplements have been reported to be ≤1 µM and recent evidence in humans show that a significant portion exists as DIM metabolites with unknown pharmacological activity (20). I3C/DIM impacts cancer cells in numerous ways including inhibition of proliferation, stimulation of apoptosis and alteration of cell cycle control (9,(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33). DIM is a weak agonist of the aryl hydrocarbon receptor (AHR) with K d of 90 nM (34).…”

Section: In Vitro Studiesmentioning

confidence: 99%

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Indoles Derived From Glucobrassicin: Cancer Chemoprevention by Indole-3-Carbinol and 3,3'-Diindolylmethane

Williams

2021

Front. Nutr.

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Hydrolysis of glucobrassicin by plant or bacterial myrosinase produces multiple indoles predominantly indole-3-carbinol (I3C). I3C and its major in vivo product, 3,3'-diindolylmethane (DIM), are effective cancer chemopreventive agents in pre-clinical models and show promise in clinical trials. The pharmacokinetics/pharmacodynamics of DIM have been studied in both rodents and humans and urinary DIM is a proposed biomarker of dietary intake of cruciferous vegetables. Recent clinical studies at Oregon State University show surprisingly robust metabolism of DIM in vivo with mono- and di-hydroxylation followed by conjugation with sulfate or glucuronic acid. DIM has multiple mechanisms of action, the most well-characterized is modulation of aryl hydrocarbon receptor (AHR) signaling. In rainbow trout dose-dependent cancer chemoprevention by dietary I3C is achieved when given prior to or concurrent with aflatoxin B1, polycyclic aromatic hydrocarbons, nitrosamines or direct acting carcinogens such as N-methyl-N'-nitro-nitrosoguanidine. Feeding pregnant mice I3C inhibits transplacental carcinogenesis. In humans much of the focus has been on chemoprevention of breast and prostate cancer. Alteration of cytochrome P450-dependent estrogen metabolism is hypothesized to be an important driver of DIM-dependent breast cancer prevention. The few studies done to date comparing glucobrassicin-rich crucifers such as Brussels sprouts with I3C/DIM supplements have shown the greater impact of the latter is due to dose. Daily ingestion of kg quantities of Brussels sprouts is required to produce in vivo levels of DIM achievable by supplementation. In clinical trials these supplement doses have elicited few if any adverse effects. Sulforaphane from glucoraphanin can act synergistically with glucobrassicin-derived DIM and this may lead to opportunities for combinatorial approaches (supplement and food-based) in the clinic.

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Section: Pharmacokinetics Of Dim In Rodents and Humansmentioning

confidence: 92%

Section: Pharmacokinetics Of Dim In Rodents and Humansmentioning

confidence: 97%

Section: Pharmacokinetics Of Dim In Rodents and Humansmentioning

confidence: 97%

Section: In Vitro Studiesmentioning

confidence: 99%

Section: In Vitro Studiesmentioning

confidence: 99%

See 3 more Smart Citations

Indoles Derived From Glucobrassicin: Cancer Chemoprevention by Indole-3-Carbinol and 3,3'-Diindolylmethane

Williams

2021

Front. Nutr.

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Protective effect of diindolylmethane‐enriched dietary cabbage against doxorubicin‐induced cardiotoxicity in mice

Natesh,

Mondal,

Penta

et al. 2024

J of Applied Toxicology

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Chemotherapy with doxorubicin (Dox) can lead to cardiotoxic effects, presenting a major complication in cancer therapy. Diindolylmethane (DIM), derived from cruciferous vegetables like cabbage, exhibits numerous health benefits. However, its clinical application is limited because of low bioavailability and suboptimal natural concentrations in dietary sources. To address this limitation, we developed a processing methodology, specifically fermentation and boiling, to enhance DIM levels in cabbage. High‐performance liquid chromatography (HPLC) analysis revealed a threefold DIM increase in fermented cabbage and a substantial ninefold increase in fermented‐boiled cabbage compared to raw cabbage. To evaluate the clinical implications, we formulated a DIM‐enriched diet and administered it to mice undergoing Dox treatment. Our in vivo results revealed that Dox treatment led to cardiotoxicity, manifested by changes in body and heart weight, increased mortality, and severe myocardial tissue degeneration. Dietary administration of the DIM‐enriched diet enhanced antioxidant defenses and inhibited apoptosis in the cardiac tissue by interfering with mitoptosis and increasing antioxidant enzyme expression. Interestingly, we found that the DIM‐enriched diet inhibited the nuclear translocation of NF‐kB in cardiac tissue, thereby downregulating the expression of inflammatory mediators such as TNF‐α and IL‐6. Further, the DIM‐enriched diet significantly reduced serum cardiac injury markers elevated by Dox treatment. These results suggest that the DIM‐enriched cabbage diet can serve as a complementary dietary intervention for cancer patients undergoing chemotherapy. Further, our research highlights the role of plant‐based diets in reducing treatment side effects and improving the quality of life for cancer patients.

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Cannabinoid receptors type 2: Function and development in agonist discovery from synthetic and natural sources with applications for the therapy of osteoporosis

Hu,

Cheng,

Chen

et al. 2024

Arabian Journal of Chemistry

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3,3′-Diindolylmethane Exhibits Significant Metabolism after Oral Dosing in Humans

Cited by 18 publications

References 58 publications

Indoles Derived From Glucobrassicin: Cancer Chemoprevention by Indole-3-Carbinol and 3,3'-Diindolylmethane

Indoles Derived From Glucobrassicin: Cancer Chemoprevention by Indole-3-Carbinol and 3,3'-Diindolylmethane

Protective effect of diindolylmethane‐enriched dietary cabbage against doxorubicin‐induced cardiotoxicity in mice

Cannabinoid receptors type 2: Function and development in agonist discovery from synthetic and natural sources with applications for the therapy of osteoporosis

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