Following on from recent I3C posts, I thought I would review the literature.
Plants have evolved protective mechanisms to deal with environmental insult. The greatest such insult, of course, is to be eaten. So, along with the chemicals that are considered to be protective in humans, such as the polyphenols, we also have chemicals that are anti-nutrients. Grazing herbivores learn to avoid or eat lightly of the latter.
Some (human) diets exclude all nightshade plants (tomatoes, peppers, eggplant, etc.) Basically because of the glycoalkaloid solanine - which is why we are warned not to eat green potatoes. People with thyroid issues may avoid cruciferous vegetables, because of goitrogens, which interfere with iodine uptake.
Protective chemicals in intact cruciferous plants are in the form of glucosinolates. Separate from glucosinolates is the enzyme myrosinase. When cell damage occurs & the enzyme comes in contact with the glucosinolates, the active chemicals are freed from the glucose component. One such family of chemicals include the thiocyanates, which act as pesticides - & are goitrogenic.
I'm not warning against cruciferous vegetables, but a supersized kale smoothie three times a day may be unwise. Similarly, when we use high-dose supplements, it's a good idea to be aware of the biological fate of those chemicals within the body.
Many here will be aware that cooking cruciferous vegetables destroys myrosinase. Stomach acid does not itself free-up the active components of glucosinolates. Anyway, while munching on your raw veggie, the glucosinolate glucobrassicin will be split into glucose & a highly unstable chemical, which ultimately leads to thiocyanate & I3C.
Complex stuff happens in the acidic environment of the stomach to form acid condensation products, that include 3,3'-diindolylmethane (DIM), 5,11-dihydroindolo-[3,2-b]carbazole (ICZ), a cyclic triindole (CT), & many more. We all know about DIM, but are those other products useful?
Note that cell studies that use I3C directly are not useful if the I3C doesn't go through a similar transformation - so I will not discuss them.
[1] 2005 - U.S.
Copenhagen rats (what other rat would they use in Valhalla?) were "treated with I3C that was administered either intraperitoneally or intravenously, in order to achieve maximal systemic exposure. This was a departure from the traditional chemopreventive route of indole-3-carbinol where the compound was incorporated in the diet." Smart decision.
"Our results indicate that I3C inhibited the incidence, growth and metastases of MAT-LyLu cells" in the rats.
Unfortuately, we only have access to I3C in oral form. I wouldn't care to improvise intraperitoneal delivery. But perhaps it could be dissolved in DMSO (dimethyl sulfoxide) & applied to the skin?
[2] 2008 - U.S. (Bradlow)
"Assessment of the oral use of indole-3-carbinol (I3C) as a chemoprotective compound has not sufficiently considered the chemical instability of I3C. This review addresses the question of whether I3C is directly active in its own right or only serves as a precursor, with all of the biological responses coming from reaction products arising in culture media and in the presence of stomach acid. Because of the rapid conversion of I3C into its dimer. diindolylmethane (DIM), and trimers very little circulating I3C is present following oral use to effect a biological response. Reports of toxicity associated with oral use of I3C relate to unfavorable enzyme induction, which can be attributed to non-DIM reaction products. Because DIM provides a predictable, safer response than the mélange of compounds derived from I3C DIM should be regarded as the chemoprotective compound of choice."
"In studies going back to early work by Wattenberg, it was shown that compounds present in cruciferous vegetables had potent anticancer activity (1). In crucifers, active phytochemicals are derived from precursor glucosinolates in plant cells through the action of myrosinase enzymes. Chemical analysis showed that the activity could be accounted for by two groups of metabolites: the indole derivatives originating from glucobrassinin and the various isothiocyanates including phenethylisothiocyanate from gluconasturtun, and sulforaphanes derived from glucorafanin. The indoles are unique in that they have already been used therapeutically and will be the focus of this review. Most attention has been given to indole-3-carbinol (I3C) as an estrogen-modulating cancer chemopreventive, despite in vivo evidence of ovarian toxicity (2) and tumor promotion (3, 4). Less attention has been directed to 3,3’-diindolylmethane (DIM), a stable product, which is formed from I3C both in vitro and in vivo..
"While the idea of obtaining these compounds from the consumption of cruciferous vegetables ( e.g. broccoli, cabbage, cauliflower and mustard greens) seemed attractive, the concentration of these compounds present in plants is actually highly variable depending on factors such as the seed strain, myrosinase enzyme activity, rainfall, soil and amount of sunlight. As a result, vegetable or seed extracts are not a practical way to get the daily amounts of these compounds required to be effective. Consequently, most investigators have turned to semisynthetic sources of cruciferous indole compounds, particularly I3C and DIM."
...
"I3C given orally is almost immediately converted to a number of condensation products in the stomach in varying proportions depending upon the exact pH. These include a dimer (DIM), trimers including the linear trimer (LTR) 2,3-bis-[3-indolyl- methyl]indole; and the cyclic trimer (CTR) (5,6,11,12,17,18- hexahydrocyclonal [1,2-b: 4,5-b’:7,8-b:]triindole), the closed ring dimer indolocarbazole (ICZ) [indolo[3,2-b]carbazole], and ascorbigen, the condensation product of I3C and ascorbic acid. Although DIM predominates, variable amounts of the other products are also formed depending on the exact pH in the stomach or in culture media. At least one of the condensation products (CTR) has shown growth promoting proestrogenic responses and would not be protective"
...
"In human testing, no I3C was found in the plasma even at the earliest 1 hour time point tested after giving single one-time doses up to 17 mg/kg of oral I3C to human volunteers"
[3] 2010 - U.S. (Bradlow & Zeligs) ... Zeligs is the BR-DIM originator.
The major point is that in cell culture medium, I3C spontaneously forms DIM (but not the other low-pH products.)
"Because of the greater biologic potency of DIM when studied in parallel with I3C in vitro, this extent of dimerization shows that DIM rather than I3C is the active agent in cell culture studies."
-Patrick
[1] ncbi.nlm.nih.gov/pubmed/155...
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