Indole-3-carbinol inhibition of androgen receptor

[el_duterino]

http://www.ncbi.nlm.nih.gov/sites/entre ... s=15958518

Indole-3-carbinol inhibition of androgen receptor expression and downregulation of androgen responsiveness in human prostate cancer cells.

Hsu JC, Zhang J, Dev A, Wing A, Bjeldanes LF, Firestone GL.

Department of Molecular and Cell Biology, The University of California at Berkeley, CA 94720, USA.

Indole-3-carbinol (I3C), a naturally occurring compound found in vegetables of the Brassica genus, such as broccoli and cabbage, is a promising anticancer agent previously shown to induce a G(1) cell-cycle arrest in the cells of human lymph node carcinoma of prostate (LNCaP) through regulation of specific G(1)-acting cell-cycle components. Since the androgen receptor (AR) mediates proliferation and differentiation in the prostate and is expressed in nearly all human prostate cancers, the effects of I3C on AR expression and function were examined in LNCaP cells. Immunoblot and quantitative RT-PCR assays revealed that I3C inhibited the expression of AR protein and mRNA levels within 12 h of indole treatment. I3C downregulated the reporter activity of LNCaP cells transiently transfected with an AR promoter-luciferase plasmid, demonstrating that a unique response to I3C is the inhibition of AR promoter activity. In contrast to I3C, the natural I3C dimerization product 3,3'-diindolylmethane, which acts as an androgen antagonist, had no effect on AR expression. To determine the functional significance of the I3C-inhibited expression of AR, the AR-regulated prostate specific antigen (PSA) was utilized as a downstream indicator. I3C downregulated the expression of PSA transcripts and protein levels and inhibited PSA promoter activity, as well as that of a minimal androgen responsive element containing reporter plasmid. Expression of exogenous AR prevented the I3C disruption of androgen-induced PSA expression. Taken together, our results demonstrate that I3C represses AR expression and responsiveness in LNCaP cells as a part of its antiproliferative mechanism.

*****************************
Could that I3C be considered for hair loss ? at least the drug is readily and cheapily avaialble at supplements stores..maybe we could think about a topical in the same line of work than ASC-J9 or Fluridil.

Any thoughs ?

 

[michael barry]

interesting.

sounds a lot like the lavender/tea tree effect on androgen receptors



now I know why after I eat alot of broccholi or cauliflower or cabbage I get a little tummy upset , etc.......



I wonder if the indole 3dc that you can buy at health food stores is soluble in alchohol and can be made into a topical? Interesting.


I guess somebody would have to make a topical out of it, and apply it and see if it reduced sebum with sebutape or reduced body hair growth after several months..............bout the only way any of us would find out.

 

[purecontrol]

You could not use I3C, you would have to use DIM

 

[harold]

DIM does not have the same effect.
" As shown in Figure 1B and C, I3C treatment strongly downregulated the production of AR protein. In contrast, DIM or TRYP had no effect on AR levels."
I find this very interesting. Now that I am a little more dubious about the use of green tea/EGCG as my fave topical antiandrogen I am onthe hunt for alternatives. DIM does seem to be a "strong" androgen antagonist howeverwhile I3C is not as strong an antagonist according to this study.
http://www.ncbi.nlm.nih.gov/pubmed/1818 ... d_RVDocSum
hh

 

[harold]

Some more...
"To determine the cellular consequences of the I3C downregulation of AR expression, production of the well characterized AR downstream target gene PSA was examined in indole-treated and untreated LNCaP cells. In these cells, the endogenous AR is mutated and can be activated by growth factors in the serum (9). Therefore, additional androgens do not need to be added to induce AR activity. Western blot analysis of cells treated with or without I3C for 24 and 48 h showed that I3C inhibited PSA protein production by 5-fold (Figure 3A). Tryptophol had no effect on PSA protein levels, demonstrating that this response was not a generalized indole effect. DIM inhibited the level of PSA protein despite the fact that DIM had no effect on AR protein expression. However, our previous studies revealed that DIM acts as a natural AR antagonist and thereby inhibits AR function (34). Since AR stimulates PSA transcription, quantitative RT–PCR was performed to measure the levels of PSA mRNA produced in indole-treated and untreated LNCaP cells (Figure 3C). Treatment with I3C or DIM rapidly decreased PSA transcript levels, with the near maximal response detected by 24 h of indole treatment. Thus, I3C and DIM each disrupt PSA expression, but through distinct mechanisms involving either the inhibition of AR expression (via I3C) or inhibiting AR function as an antagonist (via DIM)."
hh

 

[squeegee]

Good job guys! as usual

 

[el_duterino]

DIM is an Androgen Antagonist, like Flutamide , biculatamide or cyperone acetate.

I found a very interesting article on how it compares to biculatamide and cyperone acetate and DHT in binding to the AR.
http://www.jbc.org/cgi/reprint/278/23/21136.pdf

I3C does not bind much to the AR but does inhibit the AR.

So both DIM and I3C molecules might have a potential effect on androgenic alopecia but work in different ways.

However, perhaps DIM does not have all the strong side effects (libido, tiredeness) associated with the other readily avaialable androgen antagonists.

We should also find out if it could have sufficient local binding effect to the AR in the follicules if used as a topical, and what vehicle could be used.

 

[abcdefg]

Where can you buy a reliable supplement of DIM? the problem is no one does any major studies on any of these when lots of this has potential.

 

[amsch]

So you guys think it's totally safe to take DIM? Even if you had bad hormonal issues while on finasteride?

I'm thinking about trying DIM myselft.

 

[harold]

If you are taking enough DIM orally for it to effect your hair then it is going to effect everything else one would think.

does anyone know if I3C or DIM have a particular smell. cos this insired me to pick up some broccoli and cabbage and extract some of this stuff through boiling water.....not a great smell.
hh

 

[purecontrol]

You want to order it from Beyond a Century, if you do decide to go with just I3C do not get the form that is mixed with the flax seed lignans.

Also do your research as I3C converts to DIM in the intestines, but that conversion will possibly vary to a great deal depending on the health of your intestines and the kind and number of bacteria in there.


So if nothing else you could combine them, but a probiotic would be a very good idea

 

[purecontrol]

There is some evidence that 2-hydroxyestrone increases sex hormone-binding globulin.(28) SHBG binds testosterone and makes it unavailable to interact with muscle and other tissues. If this occurs, the relative effects of I3C/DIM would be even more pronounced, resulting in not only lower total T levels, but also less functional levels of testosterone

 

[harold]

You want to order it from Beyond a Century, if you do decide to go with just I3C do not get the form that is mixed with the flax seed lignans.

Also do your research as I3C converts to DIM in the intestines, but that conversion will possibly vary to a great deal depending on the health of your intestines and the kind and number of bacteria in there.


So if nothing else you could combine them, but a probiotic would be a very good idea

I would love to be able to order from Beyond a Century but I live in Australia and they dont do international deliveries. Still at least for this product (unlike others) there are other sources.

From what I have read though I was under the impression that the conversion to DIM took place in the stomach and it was acid that was responsible for the conversion.

But yeah a combination of a decent androgen antagonist (DIM) and a repressor of androgen expression (I3C) sounds pretty potent. From the paper the effect of DIM vs I3C on androgen response seemed to be about the same despite theis different methods of action. Only question then is how much systemic effect is there? An inverse association between the intake of broccoli/cauliflower and prostate cancer has been found in at least some studies so it seems that some systemic effect is possible. I suspect this stuff to be a fair bit stronger stuff than green tea.
Cant stand the smell of boiled broccoli though. uke:
hh

 

[larry27]

looks better take this oral


Further evidence suggests that I3C must be exposed to stomach acid to exert its full effects.11–15 For this reason, individuals with low stomach acid, such as those taking H2blockers (e.g., Zantac/ranitidine) or proton pump inhibitors (e.g., Prilosec/omeprazole), may not benefit as much from I3C.

http://healthlibrary.epnet.com/GetConte ... kiid=21757

 

[harold]

No. Do not take it orally. The exposure to stomach acid actually converts I3C to other substances like DIM.
As for more evidence that this stuff is potentially active in vivo and even more reason NOT to take it orally (unless you dont worry about sides as much as you worry about hair) is this excerpt from the link you provided.
"Studies in rats, chickens, guinea pigs, mice, and dogs suggest that I3C is safe at recommended doses.24 Human trials have found no significant side effects with I3C.25,26,27
However, one study of rats found increased abnormalities in male offspring, specifically related to their fertility.35"
So it looks like it interfered with androgen receptor expression pretty efffectively.
hh

 

[squeegee]

Harold, I am taking it ( DIM) everyday since 4 months. No smell at all, green color pills.

 

[amsch]

Harold, I am taking it ( DIM) everyday since 4 months. No smell at all, green color pills.

Did it have any effect? Hair, body, general..

 

[squeegee]

Harold, I am taking it ( DIM) everyday since 4 months. No smell at all, green color pills.

Did it have any effect? Hair, body, general..

No shedding, no nothing.. about hair..no more acne and dryer skin..I lost bodyfat like crazy too.. but I am taking a shitload of other stuff at the same time too..
Good info on DIM BTW:

Guy from another hairloss forum


I know several people have been patiently waiting to see my results after 6 weeks on DIM.

The day before starting DIM supplementation, I sent in a saliva based hormone test for Estradiol. After 6 weeks, I sent in another test for Estradiol.

First test results:

Estradiol: 2.1pg/ml (expected range 0.5-1.5) *high

Second test results (after taking DIM for 6 weeks):

Estradiol: .8pg/ml

For the record I've been taking 400mg of DIM each day. 200mg in the morning and 200mg at night.

This is looking good!



http://www.aapspharmaceutica.com/mee...Symposiium.pdf
http://www.dimfaq.com/site/articles.htm

According to people on every ACNE forums over the internet.. DIM is stronger than Accutane.



Indole-3-carbinol byproduct acts as antiandrogen to halt prostate cancer cell growth

In a study funded in part by the National Institutes of Health, to be published in the June 6 2003 issue of the Journal of Biological Chemistry, University of California, Berkeley researchers have found that a digestive product of indole-3-carbinol, which occurs naturally in broccoli and other cruciferous vegetables, halts the growth of prostate cancer cells in vitro. The compound, 3,3’-diindolymethane (DIM), inhibits androgenic hormones that fuel prostate cancer growth. Although androgen is important for the normal development of the prostate, it is believed to be involved in the early stages of prostate cancer.

The researchers administered DIM to androgen dependent and androgen independent prostate cancer cells and found that androgen-dependent cells experienced a 70 percent reduction in growth compared to those that did not receive the compound. Androgen-independent prostate cancer cells were not affected by DIM. The scientists went on to discover that DIM inhibited dihydrotestosterone, the primary androgenic hormone that is believed to be the culprit in prostate cancer. Dihydrotesterone stimulates prostate specific antigen, or PSA, which is elevated in prostate cancer. When DIM was administered to the androgen-dependent prostate cancer cells, PSA levels dropped.

A study of the molecular structure of DIM showed that it is similar to the androgen-blocking drug Casodex. Lead author Hien Le, PhD, explained, “DIM works by binding to the same receptor that DHT uses, so it's essentially blocking the androgen from triggering the growth of the cancer cells."

Principle researcher and professor nutritional sciences and toxicology at UC Berkeley's College of Natural Resources, Leonard Bjeldanes, summarized, "As far as we know, this is the first plant-derived chemical discovered that acts as an antiandrogen. This is of considerable interest in the development of therapeutics and preventive agents for prostate cancer."

—D Dye


May 16, 2003


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.

 

[el_duterino]

Hey guys, just a quick update on I3c. I did buy a bottle of 60 caps, 200mg of Indole-3-carbinol by NOW foods.

I started to mix a topical using 96% alcohol, Polish rectified spirit...

This Indole-3-carbinol stinks so bad that I stopped..there is just no way someone would put it on his scalp.

It smells like a putrified dead body ..kind of hard to explain but impossible to consider as a topical. And the smell is very lasting, even after I washed the glass mixing equipments the smell persisted.

 

[gjp2222]

If you are looking for the best DIM supplement on the market, consider using this product. I began using it Feb this year as a method of offsetting some of the finasteride sides. Not only did it accomplish this but it has improved my hair, much thicker with increased growth in crown area. It has also improved my general health including leaning me out a bit and better skin texture. Its not cheap but it is the most technically advanced DIM supplement around. Guess you get what you pay for.

http://www.activamune.com/product.htm