Plant indoles, also called glucosinolates, found in cruciferous vegetables provide health benefits to humans. Cruciferous vegetables are known for their cancer protection. Two such indoles provided by cruciferous vegetables are I3C (Indole 3 Carbinol) and DIM (Diindolylmethane). DIM is not naturally present in these plants. It gets released with the help of enzymes upon crushing of the broccoli, cauliflower, cabbage or brussel sprouts or during human digestion.1,3 Stomach acid, or HCl, can also aid the joining of two indole 3 carbinols to make diindolylmethane. Lack of HCl will hinder one's ability to make DIM from I3C.2
So basically, DIM is 2 molecules of I3C combined together. I3C in a capsule is not shelf stable because it is sensitive to light, heat and moisture. I3C is irritating to the stomach and research tells us that it can have very negative side effects in doses over 300 mg daily such as dizziness and unsteady gait which may be due to nervous system toxicity. One study shows evidence that 90% of orally consumed I3C converts to other compounds. Perhaps it is these other compounds that cause these side effects. One compound I3C converts to is ICZ, or indololcarbizol. This compound causes DNA damage.4 DIM studies show no toxicity when given triple the dose in humans.
What Actions Does DIM Have on the Body that Make it Beneficial to our Health?
It has been suggested that a low level of the 2-hydroxyestrogen metabolites (2-OHE) and a high level of 16 alpha-hydroxyestrone (16 alpha-OHE1) is associated with an enhanced risk of breast cancer. DIM increases 2 hydroxyestrone and therefore improves the 2/16 hydroxyestrone ratio, making it very protective for women at high risk for this condition.6
Research by Bradlow says that DIM also reduces availability of 4-androstenedione for aromatization to estrone.7 He concludes that DIM is more potent than I3C at protecting against mammary carcinoma due to decreased formation of 16 alpha-hydroxyestrone from estrone.6
What About Toxicity Studies?
In acute toxicity studies in mice “DIM produced no observable 24-hr acute toxicity up to 4 g/kg body weight, except for a slight decrease in haematocrit. However, I-3-C exhibited a dose-dependent toxicity above 100 mg/kg body weight, including a decrease in hepatic reduced glutathione after 2 hr and severe neurological toxicity, and the release of liver enzymes to the plasma at 24 hr.”9
Bottom Line: Supplementation of DIM should be recommended over supplementation of I3C for safety purposes.
DIM is a More Potent Antioxidant Than I3C
When tested side by side with I3C, DIM was shown to be a more potent antioxidant with greater activity than vitamin E because of its hydrogen (electron) donating ability.
Should we Just Eat Cruciferous Vegetables?
Eating 2 pounds of cruciferous vegetables like raw cabbage or broccoli can ultimately supply, via I3C conversion into DIM, about 20-30 mg of DIM. Therefore, supplementation is ideal along with eating cruciferous vegetables.
What Does DIM Do?
Research clearly shows that 4 hydroxy estrogen and 16 hydroxy estrogen are not favorable when elevated. Many doctors are now performing clinical tests on their patients to screen for risk of breast cancer such as the Estronex™ test offered by MetaMetrix Labs. Low risk for breast cancer is marked by a high 2/16 ratio (2 hydroxy to 16 hydroxy estrogen). It is clearly established by research that DIM raises the 2/16 ratio without elevating 4 hydroxy estrogen. DIM helps men too because it is an aromatase inhibitor. DIM helps to block the conversion of testosterone to estrogen.10 Regarding dosing, I3C needs to be given at 3-4 times the dosage of DIM to provide the same positive benefits. (Note: 300-400 mg I3C as compared to 60-100 mg DIM). I3C in low doses, like the amounts found in cruciferous vegetables is safe. I3C ingested at higher doses needed to shift estrogen ratios may be problematic.
Can DIM be Taken with Medications?
DIM is safe when taken with Tamoxifen, birth control pills and other herbs such as St. John’s Wort that affect cytochrome p450 enzymes. Because of its effects on CYP enzymes, I3C should not be taken with any of these. I3C blocks ovulation, can interfere with birth control pills and may alter the effects of many herbs such as St John's Wort and could lead to Tamoxifen toxicity if taken simultaneously. Researchers in Minneapolis, MN found that DIM does not effect the metabolism of Tamoxifen. I3C on the other hand, converts Tamoxifen into N-desmethyl-Tamoxifen 3 fold, which itself gets transformed into a genotoxic metabolite.13 Research titled Endocrine Disruption by I3C and Tamoxifen: Blockage of Ovulation may be disturbing to some. This is a quote from the Gao ovulation study: “In the current study, I3C disrupted ovulation already at doses that did not elicit systemic toxicity as indicated by a lack of reduced body weight gain, which was then observed at higher doses.” Gao asserts that “I3C appears to have TCDD-like inhibitory effects on ovulation.”14 TCDD is a heavy duty dioxin chemical. Researchers in Denmark state “Indolo[3,2- b]carbazole (ICZ), which is formed in the acidic environment of the stomach after intake of I3C, has a similar structure to, and shares biological effects with, the well-known tumor promoter 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD).” This is the conclusion of their study: “Further studies are needed in order to clarify the anticarcinogenic/carcinogenic effects of I3C and ICZ before high doses of I3C may be recommended as a dietary supplement.” They feel that ICZ's tumor promoting activity is due to its activation of the Ah receptor and stimulation of certain cytochrome p450 enzymes mainly Cyp1a1, Cyp1a2 and Cyp1b1.15
DIM's proven safety means that DIM can be used by women wishing to get pregnant but should be discontinued during pregnancy and lactation. There are no known contraindications for DIM supplementation.
Should Men Take DIM?
Men who wish to prevent prostate cancer and men with a family history of prostate cancer should take DIM. Research published in the British Journal of Cancer, 2004 states “Prostate cancer mortality results from metastases to the bones and lymph nodes and progression from androgen-dependent to androgen-independent disease. Although androgen ablation was found to be effective in treating androgen-dependent prostate cancer, no effective life-prolonging therapy is available for androgen-independent cancer.” Results of this study suggest that DIM induces apoptosis in PC3 cells, through the mitochondrial pathway suggesting that DIM is hopeful as a therapeutic strategy for the treatment of androgen-independent prostate cancer.11 According to UC Berkeley researchers “DIM exhibits potent antiproliferative and antiandrogenic properties in androgen-dependent human prostate cancer cells. DIM suppresses cell proliferation of LNCaP cells and inhibits dihydrotestosterone (DHT) stimulation of DNA synthesis.” DIM is a strong competitive inhibitor of DHT binding to the androgen receptor. This study is titled: Plant-derived 3,3_- Diindolylmethane Is a Strong Androgen Antagonist in Human Prostate Cancer Cells.10 An in vivo study in rats showed that DIM cut in half testosterone 16 alpha and 2 alpha-hydroxylation.12
DIM absorption can be greatly enhanced by emulsifying it with lecithin in rice bran oil, including with it compounds that hold it in solution such as beeswax, and finally adding fat-soluble nutrients that aid absorption through the gut wall. DIM-Avail is a unique combination of such ingredients. DIM-Avail uses the same proven technology of Designs for Health's Q-Avail, recently shown in human subjects to have far superior bioavailability and peak absorption rates in comparison to powdered CoQ10 and sublingual forms.
Why Choose DIM over I3C? by Linda Lizotte, RD, CDN and Camille Rush, CN, CNC
Studies show that the benefits of Dindolymethane (DIM) outweigh those of its precursor Indole-3-Carbinol (I3C) in terms of absorbability, safety, and potency. Regarding dosing, I3C needs to be given at 3-4 times the dosage of DIM to provide the same positive benefits. (Note: 300-400 mg I3C as compared to 60-100 mg DIM). The higher the dose if I3C, the greater the probability is that it effects liver enzymes and can cause toxicities with common medications such as Tamoxifen. Moreover, DIM was shown to be a very potent antioxidant, even more potent than vitamin E due to its H donating ability.
If only selected positive studies on I3C were analyzed, it would appear that I3C prevents breast cancer and tumors and that it improves the 2/16 hydroxyestrogen ratio. If all studies were examined, however, it would be apparent that it is not a good idea to supplement high doses of I3C because multiple studies show that by increasing 4 hydroxyestrogen and initiating the Ahr receptor, I3C is a tumor promoter in many organs. As a matter of fact, I3C has been shown to cause endometrial adenocarcinoma, thyroid cancer, liver cancer, and pancreatic cancer. (Dashwood 1998) Finally, I3C increases COX enzymes and PGE2.
Because I3C inhibits mammary gland carcinogenesis in animal models and induces estradiol 2-hydroxylation in humans, the breast is the target organ of highest clinical interest for I3C; phase II clinical efficacy studies of I3C breast cancer chemoprevention are underway at the NCI (Kelloff et al., 1996a). Based on studies that show clear evidence of I3C promotion or enhancement of carcinogenesis as well as the ability of I3C to activate procarcinogens, some researchers have expressed reservations concerning extensive use of I3C in humans (Shertzer & Sainsbury, 1991;Preobrazhenskaya & Korolev, 1992; Dashwood 1998.
DIM does everything positive that I3C does but with none of the negative side effects because it does not increase 4 hydroxyestrogen and nor does it stimulate the ary hydrocarbon receptor, both of which are responsible for the negative side effects of I3C.
In terms of safety, consider the following examples:
a. Beagle dogs given 100 mg/kg of I3C exhibited anorexia, dehydration, weight loss, diarrhea and vomiting.
b. Guinea pigs given as little as .3 mg/kg of I3C exhibited moderate depression, trembling, tachypnea (also known as polypnea = rapid breathing), irregular breathing and hepatic steatosis.
c. Mice of approximately 100 mg/kg body weight showed signs of neurological impairment upon I3C ingestion.
d. In one human trial women were given 50-400 mg I3C for 4 weeks. Two of the women experienced an increase in SGPT liver enzyme.
DIM does not interfere with medications like I3C does and does not block ovulation. Many cancer studies were performed on DIM and I3C involving Tamoxifen.
e. Women on tamoxifen (post breast cancer treatment) should not take I3C. While I3C can enhance liver carcinogenicity of tamoxifen, DIM has been shown to have no effect. This study showed that DIM is not a proximate intermediate in the mechanism of action of I3C in that “treatment with DIM yielded no changes in tamoxifen metabolism by hepatic microsomes.” “Thus, treatment of rats with I3C may increase the level of tamoxifen derived DNA adducts in the liver and hypothetically lead to increased hepatocarcinogenicity of TAM (tamoxifen).”
f. I3C blocks ovulation as shown in “Endocrine Disruption by I3C and Tamoxifen: Blockage of Ovulation” by Gao. “In the current study, I3C disrupted ovulation already at doses that did not elicit systemic toxicity as indicated by a lack of reduced body weight gain, which was then observed at higher doses.” Gao asserts that “I3C appears to have TCDD-like (this is a heavy duty dioxin chemical) inhibitory effects on ovulation.” “Past studies have attributed the chemopreventive properties of I3C to its acid reaction product, DIM. DIM has much lower affinity to the aryl hydrocarbon receptor (AhR) than TCDD.” ‘Nevertheless, DIM induces CYP1A1 gene expression in MCF-7 (breast cancer) cells and oral administration of this compound at very low doses (d mg/kg every other day) resulted in inhibition of tumor formation in the demethylbenzantracene-induced rat mammary tumor model (Grubbs 1995). The same study suggested that the antiestrogenic effects of DIM occurred at concentrations 10 -100 times lower than those needed to induce hepatic CYP1A1 dependent enzyme activity (Chen 1998). In our study, body weight, ovarian weight, or ovulation were not affected even at the highest dose of DIM studied. This finding is inconsistent with the claim that DIM is the biologically active metabolite of I3C with regard to its antiestrogenicity.
“In summary, both the ER antagonist tamoxifen and the AhR agonist I3C blocked ovulation and disrupted the preovulatory surge in LH and FSH in the gonadotropin-primed immature rat model. The effect of I3C on ovulation and gonadotropin secretion prior to ovulation was similar to the action of TCDD (dioxin compound) in that reduced ovulation was not fully restored by exogenous hCG, indicating direct actions of I3C on the preovulatory ovary in addition to DISRUPTION OF THE HYPOTHALAMIC-HYPOPHYSEAL AXIS.”
Another study showed that TCDD induces ovarian tumors. Remember that I3C acts in a similar way. It is likely that I3C interferes with the action of BCPs. No adverse interactions were seen with DIM and oral contraceptives in the study by Stresser (this study used BioResponse DIM, same patented form that is in FemGuard + Balance and compared it to I3C) “Report: Examination of potential for absorbable DIM to induce and inhibit cytochrome p450 isoforms.”
Who should take DIM?
DIM has been shown to be cancer preventive, reduce the risk of breast cancer, improve endometriosis, cervical dysplasia, PMS symptoms, and symptoms of perimenopause. Women on HRT benefit from DIM supplementation as well as men with estrogen related conditions like prostate hypertrophy. DIM may be an aromatase inhibitor.
Who should take therapeutic doses of I3C beyond what they get in their cruciferous vegetables? You decide. Read the abstracts below.
Indole-3-carbinol: anticarcinogen or tumor promoter in brassica vegetables?Dashwood RH. Department of Environmental Biochemistry, University of Hawaii, Honolulu 96822, USA.
Indole-3-carbinol (I3C) is one of several compounds in brassica vegetables that demonstrate anticarcinogenic effects in experimental animals. A review of Medline and CancerLit databases indicated that interest in I3C, as a cancer chemopreventive agent, has increased significantly in the past 5-10 years. Whereas most studies report inhibitory or protective effects of I3C in vivo, a few provide clear evidence for promotion or enhancement of carcinogenesis, depending upon the initiator, exposure protocol and species. In the absence of detailed information on the inhibitory and in particular, promotional mechanisms, it would seem advisable to proceed with caution before including I3C in extensive human clinical trials.
Intrinsic acute toxicity and hepatic enzyme inducing properties of the chemoprotectants indole-3-carbinol and 5,10-dihydroindeno[1,2-b]indole in mice.
Food Chem Toxicol. 1991 Apr;29(4):237-42.
Shertzer HG, Sainsbury M.
Department of Environmental Health, University of Cincinnati Medical Center, OH 45267-0056.
Indole-3-carbinol (I-3-C) and 5,10-dihydroindeno[1,2-b]indole (DHII) have been shown to be protective against carbon tetrachloride and other chemicals that cause hepatic toxicity. In part, this protection appears to be afforded by the ability of these compounds to act as antioxidants, with DHII having much the greater efficacy. In order to understand the mechanisms of chemoprotection, as well as the potential for therapeutic and pharmaceutical use in humans, the antioxidants I-3-C and DHII were examined for their intrinsic acute toxicity, and their hepatic enzyme inducing properties in mice. The results were compared with those of the well characterized agent phenobarbital. Following treatment by gavage for 10 days with 50 mg compound/kg body weight, I-3-C produced modest (10-50%) increases in hepatic cytochrome P-450, aminopyrine N-demethylase, UDP-glucuronosyl transferase (UDPGT) and glutathione S-transferase (GST), and a four-fold increase in NAD(P)H: (quinone acceptor) oxidoreductase (quinone reductase) activity. DHII did not alter oxidative enzyme activities, but increased GST and UDPGT by about 50%, and quinone reductase over five-fold. In the acute toxicity studies, DHII produced no observable 24-hr acute toxicity up to 4 g/kg body weight, except for a slight decrease in haematocrit. However, I-3-C exhibited a dose-dependent toxicity above 100 mg/kg body weight, including a decrease in hepatic reduced glutathione after 2 hr and severe neurological toxicity, and the release of liver enzymes to the plasma at 24 hr. We conclude, on the basis of the superior antioxidation efficacy of DHII, its enzyme-inducing properties, and intrinsic toxicity, that DHII or cogeners thereof have great potential as chemoprotective or therapeutic agents. However, I-3-C does not have such potential.
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