Thoughts on I3C/DIM

[Fedor]

What are your thoughts on I3C/DIM?

It seems there is a good bit of research backing its claims to reduce the bad estrogens while keeping your good estrogens normal.

[Fedor]

bump for info on this. I see conflicting info out there on the internets.

[bigpetefox]

They are good at helping eliminate estradiol/estrone and sparing 2OHestorgens, but no substitute for an actual SERM..

[macrophage69alpha]

DIM may (debatable) increase favorable conversion to 2-hydoxyestrone, however it also appears to interfere testosterone synthesis (reducing substrate availability) and is an androgen receptor antagonist

[Fedor]

thanks guys.

[macrophage69alpha]

so might have some use in women, generally not a good idea for men. (unless you have prostate cancer)

[macrophage69alpha]

1: J Biol Chem. 2003 Jun 6;278(23):21136-45. Epub 2003 Mar 27. Links
Plant-derived 3,3'-Diindolylmethane is a strong androgen antagonist in human prostate cancer cells.Le HT, Schaldach CM, Firestone GL, Bjeldanes LF.
Department of Nutritional Sciences and Toxicology, The University of California, Berkeley, California 94720-3104, USA. lfb@nature.berkeley.edu

3,3'-Diindolylmethane (DIM) is a major digestive product of indole-3-carbinol, a potential anticancer component of cruciferous vegetables. Our results indicate that 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. These activities were not produced in androgen-independent PC-3 cells. Moreover, DIM inhibited endogenous PSA transcription and reduced intracellular and secreted PSA protein levels induced by DHT in LNCaP cells. Also, DIM inhibited, in a concentration-dependent manner, the DHT-induced expression of a prostate-specific antigen promoter-regulated reporter gene construct in transiently transfected LNCaP cells. Similar effects of DIM were observed in PC-3 cells only when these cells were co-transfected with a wild-type androgen receptor expression plasmid. Using fluorescence imaging with green fluorescent protein androgen receptor and Western blot analysis, we demonstrated that DIM inhibited androgen-induced androgen receptor (AR) translocation into the nucleus. Results of receptor binding assays indicated further that DIM is a strong competitive inhibitor of DHT binding to the AR. Results of structural modeling studies showed that DIM is remarkably similar in conformational geometry and surface charge distribution to an established synthetic AR antagonist, although the atomic compositions of the two substances are quite different. Taken together with our published reports of the estrogen agonist activities of DIM, the present results establish DIM as a unique bifunctional hormone disrupter. To our knowledge, DIM is the first example of a pure androgen receptor antagonist from plants

[macrophage69alpha]

note- DIM also acts as an inducer of aromatase (via estrogenic action)

Toxicol Sci. 2001 May;61(1):40-8. Links
2,3,7,8-Tetrachlorodibenzo-p-dioxin and diindolylmethanes differentially induce cytochrome P450 1A1, 1B1, and 19 in H295R human adrenocortical carcinoma cells.Sanderson JT, Slobbe L, Lansbergen GW, Safe S, van den Berg M.
Research Institute for Toxicology, Utrecht University, P.O. Box 80176, 3508 TD Utrecht, The Netherlands. t.sanderson@ritox.vet.uu.nl

Diindolylmethane (DIM) is an acid-catalyzed condensation product of indole-3-carbinol, a constituent of cruciferous vegetables, and is formed in the stomach. DIM alters estrogen metabolism and inhibits carcinogen-induced mammary tumor growth in rodents. DIM is a weak agonist for the aryl hydrocarbon (Ah) receptor and blocks the effects of estrogens via inhibitory Ah receptor-estrogen receptor cross-talk. DIM and various structural analogs were examined in H295R cells for effects on 3 cytochrome P450 (CYP) enzymes involved in estrogen synthesis and/or metabolism: CYP1A1, CYP1B1, and CYP19 (aromatase). Aromatase activity was measured by conversion of 1 beta-(3)H-androstenedione to estrone and (3)H(2)O. H295R cells were exposed to the test chemicals dissolved in dimethyl sulfoxide for 24 h prior to analyses. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) (0--30 nM) and DIM (0--10 microM) induced ethoxyresorufin-O-deethylase (EROD) activity, as a measure of CYP1A1 and possibly 1B1 activity, with EC(50) values of about 0.3 nM and 3 microM, respectively. DIM, but not TCDD, induced aromatase activity with an apparently maximal 2-fold increase at 10 microM; higher concentrations of DIM and many of its analogs were cytotoxic. TCDD (30 nM) significantly increased CYP1A1 and 1B1 mRNA levels, but had no effect on mRNA for CYP19. DIM (3 microM) significantly increased mRNA levels for all three CYPS: DIM analogs with substitutions on the 5 and 5' position (3 microM) induced aromatase and EROD activity, together with mRNA levels of CYP1A1, 1B1, and 19; analogs that were substituted on the central carbon of the methane group showed little or no inductive activity toward the CYPS: In conclusion, DIM and several of its analogs appear to induce CYPs via multiple yet distinct pathways in H295R human adrenocortical carcinoma cells.

[macrophage69alpha]

1: Anal Bioanal Chem. 2008 Feb;390(4):1111-9. Epub 2008 Jan 11. Links
Screening of synthetic and plant-derived compounds for (anti)estrogenic and (anti)androgenic activities.Bovee TF, Schoonen WG, Hamers AR, Bento MJ, Peijnenburg AA.
Department of Safety & Health, RIKILT-Institute of Food Safety, P.O. Box 230, 6700 AE, Wageningen, The Netherlands. toine.bovee@wur.nl

Recently we constructed yeast cells that either express the human estrogen receptor alpha or the human androgen receptor in combination with a consensus ERE or ARE repeat in the promoter region of a green fluorescent protein (yEGFP) read-out system. These bioassays were proven to be highly specific for their cognate agonistic compounds. In this study the value of these yeast bioassays was assessed for analysis of compounds with antagonistic properties. Several pure antagonists, selective estrogen receptor modulators (SERMs) and plant-derived compounds were tested. The pure antiestrogens ICI 182,780 and RU 58668 were also classified as pure ER antagonists in the yeast estrogen bioassay and the pure antiandrogen flutamide was also a pure AR antagonist in the yeast androgen bioassay. The plant-derived compounds flavone and guggulsterone displayed both antiestrogenic and antiandrogenic activities, while 3,3'-diindolylmethane (DIM) and equol combined an estrogenic mode of action with an antiandrogenic activity. Indol-3-carbinol (I3C) only showed an antiandrogenic activity. Coumestrol, genistein, naringenin and 8-prenylnaringenin were estrogenic and acted additively, while the plant sterols failed to show any effect. Although hormonally inactive, in vitro and in vivo metabolism of the aforementioned plant sterols may still lead to the formation of active metabolites in other test systems.

[macrophage69alpha]

as a note- the 2-hydroxy estrone claims of DIM and I3C are suspect, at least in models other than postmenopausal women (age 50-70).

[Fedor]

what about other plant-based anti estrogens like the chrysin derivatives and/or calcium glucerate? (the supplements which ass uses in his post-cycle supplement)

	ASS Nelson Montana

[macrophage69alpha]

chrysin has very low oral bioavailability, and the in vitro research on aromatase is conflicting (but irrelevant to oral dosing). It does have at least some estrogenic activity (though again likely irrellevant due to bioavailability).

1: J Steroid Biochem Mol Biol. 2001 Sep;78(3):231-9. Links
No evidence for the in vivo activity of aromatase-inhibiting flavonoids.Saarinen N, Joshi SC, Ahotupa M, Li X, Ammälä J, Mäkelä S, Santti R.
Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, FIN-20520, Turku, Finland. nisaarin@utu.fi

Measurements of the aromatase-inhibiting and antioxidative capacities of flavonoids in vitro showed that slight changes in flavonoid structure may result in marked changes in biological activity. Several flavonoids such as 7-hydroxyflavone and chrysin (5,7-dihydroxyflavone) were shown to inhibit the formation of 3H-17beta-estradiol from 3H-androstenedione (IC(50)<1.0 microM) in human choriocarcinoma JEG-3 cells and in human embryonic kidney cells HEK 293 transfected with human aromatase gene (Arom+HEK 293). Flavone and quercetin (3,3',4',5,7-pentahydroxyflavone) showed no inhibition (IC(50)>100 microM). None of the requirements for optimal antioxidative capacity (2,3-double bond with 4'-hydroxy group, 3-hydroxyl group, 5,7-dihydroxy structure and the orthodihydroxy structure in the B-ring) is relevant for the maximum inhibition of aromatase by flavonoids. After oral administration to immature rats at a dose of 50 mg/kg body weight, which considerably exceeds amounts found in daily human diets, neither aromatase-inhibiting nonestrogenic flavonoids, such as chrysin, nor estrogenic flavonoids, such as naringenin and apigenin, induced uterine growth or reduced estrogen- or androgen-induced uterine growth. The inability of flavonoids to inhibit aromatase and, consequently, uterine growth in short-term tests may be due to their relatively poor absorption and/or bioavailability.

1: Br J Clin Pharmacol. 2001 Feb;51(2):143-6. Links
Disposition and metabolism of the flavonoid chrysin in normal volunteers.Walle T, Otake Y, Brubaker JA, Walle UK, Halushka PV.
Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Division of Clinical Pharmacology, Medical University of South Carolina, Charleston, SC 29425, USA. wallet@musc.edu

AIMS: To describe the oral disposition of the dietary flavonoid chrysin in healthy volunteers. METHODS: Oral 400 mg doses of chrysin were administered to seven subjects. Chrysin and metabolites were assayed in plasma, urine and faeces by h.p.l.c. RESULTS: Peak plasma chrysin concentrations were only 3-16 ng ml(-1) with AUCs of 5-193 ng ml(-1) h. Plasma chrysin sulphate concentrations were 30-fold higher (AUC 450-4220 ng ml(-1) h). In urine, chrysin and chrysin glucuronide accounted for 0.2-3.1 mg and 2-26 mg, respectively. Most of the dose appeared in faeces as chrysin. Parallel experiments in rats showed high bile concentrations of chrysin conjugates. CONCLUSIONS: These findings, together with previous data using Caco-2 cells, suggest that chrysin has low oral bioavailability, mainly due to extensive metabolism and efflux of metabolites back into the intestine for hydrolysis and faecal elimination.

[macrophage69alpha]

really you are generally just better off using Aromasin or AIFM to control estrogen (for men at least)

	AIFM AI For Men uses ATD, a natural steroidal aromatase inhibitor comparable to Aromasin in results.

[macrophage69alpha]

now if you have prostate cancer or BPH then these compounds may benefit you, though the jury is still out on that one. But these compounds have NO PLACE in sports/physique enhancement.

[Fedor]

So in summary, again, the bottom line is:

1. DIM has an anti-androgen effect
2. Chrysin is not that bioavailable orally