Physiological Modeling of Formulated and Crystalline 3,3′-Diindolylmethane Pharmacokinetics Following Oral Administration in Mice

Anderton, Mark; Manson, Margaret M.; Verschoyle, Richard D.; Gescher, Andreas J.; Steward, William P.; Williams, Monique; Mager, Donald E.

doi:10.1124/dmd.32.6.632

Cited by 115 publications

(103 citation statements)

References 27 publications

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“…Compared with a pure crystalline formulation, BR-DIM is suggested to have 50% higher bioavailability. 26 The half-life of DIM ranges from 2.6 to 4.5 hours, and there is a significant increase in the maximum concentration of plasma DIM at supplementation levels between 100 and 200 mg/d. 78 The recommendation for a tolerable single dose of DIM from BR-DIM has been established as 300 mg (4.3 mg/kg/ d).…”

Section: Mechanisms Of Action and Surrogate Endpoints In Humansmentioning

confidence: 99%

“…However, after 24 hours, DIM is no longer measurable in brain tissue. 26 Metabolites of DIM are found in both human serum and urine but demonstrate significant clearance within 24 hours. 27,28 …”

Section: Metabolism Of Diindolylmethane From Indole-3-carbinolmentioning

confidence: 99%

“…Concentrations are time dependent, as demonstrated in a mouse model after supplementation with pure crystalline DIM at a dosage of 250 mg/kg. 26 vary. The highest concentration of DIM is found in the liver.…”

Section: Metabolism Of Diindolylmethane From Indole-3-carbinolmentioning

confidence: 99%

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Chemopreventive properties of 3,3′-diindolylmethane in breast cancer: evidence from experimental and human studies

Thomson

Ström

2016

Nutr Rev

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Diet is a modifiable factor associated with the risk of several cancers, with convincing evidence showing a link between diet and breast cancer. The role of bioactive compounds of food origin, including those found in cruciferous vegetables, is an active area of research in cancer chemoprevention. This review focuses on 3,3 0 -diindolylmethane (DIM), the major bioactive indole in crucifers. Research of the cancerpreventive activity of DIM has yielded basic mechanistic, animal, and human trial data. Further, this body of evidence is largely supported by observational studies. Bioactive DIM has demonstrated chemopreventive activity in all stages of breast cancer carcinogenesis. This review describes current evidence related to the metabolism and mechanisms of DIM involved in the prevention of breast cancer. Importantly, this review also focuses on current evidence from human observational and intervention trials that have contributed to a greater understanding of exposure estimates that will inform recommendations for DIM intake.

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Section: Mechanisms Of Action and Surrogate Endpoints In Humansmentioning

confidence: 99%

Section: Metabolism Of Diindolylmethane From Indole-3-carbinolmentioning

confidence: 99%

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Chemopreventive properties of 3,3′-diindolylmethane in breast cancer: evidence from experimental and human studies

Thomson

Ström

2016

Nutr Rev

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“…One percent DIM added in the AIN-76A-based diets were prepared by Research Diets Inc. (New Brunswick, NJ) and stored at −20°C. The dose was chosen based in part on studies reported previously (26,27). In the present study, around 30 mg of DIM would be estimated to be administered to each TRAMP mouse per day when consuming AIN-76 diet containing 1% DIM (1% DIM diet).…”

Section: Diet and Animal Study Designmentioning

confidence: 99%

Epigenetic Modifications of Nrf2 by 3,3′-diindolylmethane In Vitro in TRAMP C1 Cell Line and In Vivo TRAMP Prostate Tumors

Khor

et al. 2013

AAPS J

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Abstract. 3,3′-diindolylmethane (DIM) is currently being investigated in many clinical trials including prostate, breast, and cervical cancers and has been shown to possess anticancer effects in several in vivo and in vitro models. Previously, DIM has been reported to possess cancer chemopreventive effects in prostate carcinogenesis in TRAMP mice; however, the in vivo mechanism is unclear. The present study aims to investigate the in vitro and in vivo epigenetics modulation of DIM in TRAMP-C1 cells and in TRAMP mouse model. In vitro study utilizing TRAMP-C1 cells showed that DIM suppressed DNMT expression and reversed CpG methylation status of Nrf2 resulting in enhanced expression of Nrf2 and Nrf2-target gene NQO1. In vivo study, TRAMP mice fed with DIM-supplemented diet showed much lower incidence of tumorigenesis and metastasis than the untreated control group similar to what was reported previously. DIM increased apoptosis, decreased cell proliferation and enhanced Nrf2 and Nrf2-target gene NQO1 expression in prostate tissues. Importantly, immunohistochemical analysis showed that DIM reduced the global CpG 5-methylcytosine methylation. Focusing on one of the early cancer chemopreventive target gene Nrf2, bisulfite genomic sequencing showed that DIM decreased the methylation status of the first five CpGs of the Nrf2 promoter region, corroborating with the results of in vitro TRAMP-C1 cells. In summary, our current study shows that DIM is a potent cancer chemopreventive agent for prostate cancer and epigenetic modifications of the CpG including Nrf2 could be a potential mechanism by which DIM exerts its chemopreventive effects.

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“…Anderton et al (31) developed a PBPK model to characterize the pharmacokinetic properties of DIM, and the plasma pharmacokinetics and biodistribution of DIM following oral administration, in mice (31). Future studies are required to determine the serum DIM concentrations in mice fed various doses of DIM.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory effect of the low‑toxic exogenous aryl hydrocarbon receptor modulator 3'3‑diindolylmethane on gastric cancer in mice

Qian

et al. 2017

Oncol Lett

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Abstract. 3'3-Diindolylmethane (DIM) has been proved to exhibit anticancer properties in many solid tumors. In our previous study, we demonstrated that DIM inhibited SGC7901 cell proliferation by inducing apoptosis and delaying cell cycle progression. Herein, we further explored the anti-tumor effect of DIM on SGC-7901 tumor bearing mice. Tumors were excised, weighed, and tested by western blot and TdT-UTP nick-end labeling (TUNEL) assay. Blood samples were collected for biochemical analysis. The expression levels of AhR and cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1) protein were evaluated by western-blot assay. Our data show that with the increase of DIM dose (0, 5, 10, 20 mg/kg/day), AhR protein gradually decreased as CYP1A1 protein increased. The weight of the tumors found in the treated animals was significantly lower than that of the control group (0.845±0.096 vs. 1.275±0.236 g, 0.768±0.161 vs. 1.275±0.236 g, 0.607±0.106 vs. 1.275±0.236 g, P<0.05). TUNEL test showed that DIM induced increased apoptosis in the treatment groups in a dose-dependent manner. Blood tests also indicated that DIM showed no toxic effect on animal weight or liver and kidney function. These results indicated that DIM agent could be a safe and potent drug in therapy of gastric cancer. IntroductionGastric cancer (GCa) is one of the most common types of malignancy, and the third leading cause of cancer-associated mortality worldwide, with 951,000 incident cases and 723,000 mortalities in 2012 (1). The overall 5-year survival rate is low due to high recurrence rates, nodal metastasis and poor responses to chemotherapy (2). Differences in lifestyle, environment and diet may also have a role in the high incidence and mortality associated with GCa (3). The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor involved in cell differentiation and carcinogenesis, including in lung cancer (4), breast cancer (5) and prostate cancer (6). There are currently few studies involving the AhR pathway and GCa (7). Our previous study demonstrated there is significant AhR expression in human GCa cells (8), and determined that the AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) could inhibit GCa cell growth (9). Thus, AhR maybe a promising target for GCa therapy. Due to the toxic and carcinogenic effects of TCDD in humans, our previous study had suggested that the selective AhR receptor modulator 3'3-diindolylmethane (DIM) could inhibit SGC-7901 human GCa cell proliferation by delaying cell cycle progression and inducing apoptosis (10). DIM is an acid-catalyzed condensation product of indole-3-carbinol, a constituent of cruciferous vegetables (11). DIM has been identified as an anti-cancer agent involved in various solid malignancies, including ovarian (12), prostate (13), colon (14) and pancreatic cancer (15). The anti-cancer effects of DIM include suppressing cancer cell proliferation (16-18) and promoting cancer cell apoptosis (19-21). There have been few reports to date regarding the effects of DIM on GCa...

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Physiological Modeling of Formulated and Crystalline 3,3′-Diindolylmethane Pharmacokinetics Following Oral Administration in Mice

Cited by 115 publications

References 27 publications

Chemopreventive properties of 3,3′-diindolylmethane in breast cancer: evidence from experimental and human studies

Chemopreventive properties of 3,3′-diindolylmethane in breast cancer: evidence from experimental and human studies

Epigenetic Modifications of Nrf2 by 3,3′-diindolylmethane In Vitro in TRAMP C1 Cell Line and In Vivo TRAMP Prostate Tumors

Inhibitory effect of the low‑toxic exogenous aryl hydrocarbon receptor modulator 3'3‑diindolylmethane on gastric cancer in mice

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