DIM and its effect on Acne Vulgaris

Dietary indole compounds have been used for centuries in traditional Chinese medicine to treat a variety of ailments and diseases. Two indoles that have attracted recent attention for their therapeutic potential are I3C and DIM. I3C is a metabolite of glucosinolate glucobrassicin, which is a chief component of cruciferous vegetables such as broccoli, cauliflower, and brussels sprouts [1]. When digested, I3C undergoes acid hydrolysis within the gut and is converted to a series of by-products, the major one being DIM [2].  Recent studies have indicated that these compounds may play a critical role in modulating immune responses, particularly with regards to inflammation and inflammatory diseases.   In this article you will find out the relationship of DIM to the Aryl Hydrocarbon Receptor and how that influences the development of acne as a result.  You will also find out the relationship of DIM to Cytochrome p450 and how this influences keratinization.

So how does DIM help with managing Acne?

• DIM binds to the Aryl Hydrocarbon Receptor, which increases the production of CYP1A1.  CYP1A1 is involved in the synthesis of retinoids.  This increase in retinoids is of benefit because acne skins have been shown to have a decreased amount of retinoids in their skin due to CYP1A1 having a genetic abnormality.
• DIM acts as a testosterone antagonist and decreases the bioavailability of testosterone.
• DIM Inhibits mTORC which is involved in the pathogenesis of acne.

I3C and DIM have been shown to interact with numerous nuclear receptors such as the AhR, the estrogen receptor, and the androgen receptor [6], and have also been shown to modulate multiple signaling pathways.  Studies have shown the therapeutic potential of both I3C and DIM may lie in the fact that they are weak ligands for the AhR (Aryl Hydrocarbon Receptor). Think of the Aryl Hydrocarbon Receptor as the detox receptor for the body.  Its role is to get rid of toxic metabolites as quickly as possible.   The aryl hydrocarbon receptor (AhR) is a cytosolic ligand-activated transcription factor, which is present in many cell types of mammals, including humans. At the moment, there is still no consensus about the biological function of this receptor. However, it received much attention for its role in the toxicity of dioxins, especially the most potent activator 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).   The biological response to many environmental pollutants is a direct consequence of their interactions with the aryl hydrocarbon receptor.

Not only contaminants like dioxins and PAH (Poly Aromatic Hydrocarbons) can bind to the AhR, but also a large number of compounds of natural origin can bind to and activate this receptor. One of the most investigated natural AhR agonists (NAhRAs) is indole-3-carbinol (I3C), which is formed in cruciferous vegetables (Brussels sprouts, broccoli, cabbage) by an enzymatic reaction after crushing of the plant tissues.

[caption id="attachment_2350" align="aligncenter" width="448"] Green vegetables once digested are broken down into DIM and other substances[/caption]

High-performance liquid chromatography has been used in pharmacokinetic studies in mice to determine the bioavailability of I3C and DIM in various tissues. Results showed that I3C and DIM were rapidly absorbed and present in all tissues following oral administration[3]. Additional studies in humans have suggested that the bioavailability of I3C and DIM are similar to that seen in mice [3].

Recent research has uncovered that the Aryl Hydrocarbon Receptor has a physiological role for normal development. What has been discovered is that the AhR also influences the cytochrome p450.  Cytochrome P-450 is a multigenically coded family of iron containing hemoproteins that catalyzes the metabolism of exogenous as well as endogenous substrates such as fatty acids, sterols, sex steroids, glucocorticosteroids, vitamin D, leukotrienes, prostaglandines and vitamin A metabolites. They also play a key role in the metabolism of xenobiotics both in liver and in skin. Retinol, retinal and all-trans retinoic acid are inactivated to 4-hydroxy-compounds, and 4-oxo-retinoic acid to more polar metabolites by P-450 isozymes in endoplasmic reticulum.

Cytochrome p450 is involved in the regulation of retinoids and also has a role in the formation of acne vulgaris.  DIM stimulates cytochrome P450 activity through the AhR, which leads to the generation of the detoxification enzymes such as CYP1A1 and CYP1A2 [4, 5].  In clinical trials, I3C and DIM have been shown to create an antiestrogenic and antiproliferative environment. These events may in part be attributed to indole-mediated AhR activation, leading to elevated levels of cytochrome P450 isozymes and affect expression of CYP1A1 and CYP1A2 expression.  DIM also has been shown to affect the transcription of more than 100 genes in keratinocytes.   'CYP' is a host of enzymes that use iron to oxidise things, often as part of the body's strategy to dispose of potentially harmful substances by making them more water-soluble.   56% of drugs taken are cleared primarily from the body by CYP!

Increasing studies have demonstrated that diindolylmethane (DIM) inhibits mTORC1 signaling directly and indirectly.  mTORC has a direct role in the development of Acne Vulgaris.   mTORC1 stands for “the nutrient-sensitive kinase mammalian target of rapamycin complex 1”.  mTORC1 is regarded as the conductor of the ‘cellular signalling symphony’ that integrates signals of cellular energy, growth factors and amino acids. Metabolic regulations mediated by mTORC1 depend on upstream activation of the IIS (insulin/IGF (insulin-like growth factor)-like signalling and this is where diet comes into play.  The foods you eat have a direct influence on the amount of insulin released.   mTORC is directly involved with hyperproliferation of keratinocytes.  So by inhibiting mTORC we inhibit hyperkeratinisation occurring.  Emerging evidence provides credible support in favor of the potential role of bioactive products derived from ingesting cruciferous vegetables such as broccoli, brussel sprouts, cauliflower, and cabbage.

I3C and its analogues have also been shown to bind to androgen receptors (AR). DIM is a strong androgen antagonist in human prostate cancer cells. DIM exhibited potent antiproliferative and anti-androgenic properties.  It suppressed cell proliferation and inhibited dihydrotestosterone (DHT) stimulation of DNA synthesis. DIM was found to be a strong competitive inhibitor of DHT binding to the AR [7].  I3C-derived products are potent inducers of certain CYP-dependent enzyme activities [8].  I3C induces CYPIA1. 3C also induces several phase I cytochrome P450- dependent activities and their corresponding genes, including CYP1A1, CYP1A2, CYP2B1 and CYP3A1.

Polymorphisms (Abnormalities) that occur in the CYP1A1, CYP17 and TNF-α genes affects hyperkeratinzation process, sebum production and inflammation in acne vulgaris.   Several genes that may influence the occurrence of AV including gene CYP 1A1, CYP 17 and TNF-α. Research conducted in Germany showed that CYP 1A1 gene polymorphisms causing the lack of an active natural retinoids resulting in follicular hyperkeratinization resulting in acne vulgaris [11].   P450s 1A1, 1A2, 1B1 and 3A4 have been shown to be involved in the metabolism of retinoic acid [13].  Natural retinoid levels are lower in those with acne vulgaris.  This occurance is due to the increased activity of the enzyme in the metabolism and inactivation of ATRA to 4-oxo-retinoic acid, so that active natural retinoids will be reduced.  Retinoic Acid causes an increase in CYP1A1 which results in normalisation of the keratinisation of the cells.

DIM affects the development of acne by more than one pathway.  DIM inhibits mTORC which results in inhibition of hyperproliferation and a normalisation of cell growth.  DIM inhibits DHT (Dehydrotestoerone) and is a testosterone antagonist.  DIM increases CYP1A1 which is directly involved in the metabolism of Vitamin A.  This increase results in sufficient Vitamin A being present in the skin and as a result hyperkeratinisation ceases.  DIM also causes an increase in the body's natural antioxidant glutathione.  Glutathione has been found to be deficient in acne skins.  It also inhibits numerous inflammatory cytokines that are involved in acne.  The oral consumption of DIM would have positive benefits for acne.

References:

Safe S, Papineni S, Chintharlapalli S. Cancer chemotherapy with indole-3-carbinol, bis(3′-indolyl) methane and synthetic analogs. Cancer Lett. 2008; 269:326–338.

Anderton MJ, Manson MM, Verschoyle RD, et al. Pharmacokinetics and tissue disposition of indole-3-carbinol and its acid condensation products after oral administration to mice. Clin Cancer Res. 2004; 10:5233–5241

Sepkovic DW, Bradlow HL, Bell M. Quantitative determination of 3,3′-diindolylmethane in urine of individuals receiving indole-3-carbinol. Nutr Cancer. 2001; 41:57–63.

Bradfield CA, Bjeldanes LF. Effect of dietary indole-3-carbinol on intestinal and hepatic monooxygenase glutathione S-transferase and epoxide hydrolase activities in the rat. Food Chem Toxicol. 1984; 22:977–982.

Manson MM, Ball HW, Barret MC, et al. Mechanism of action of dietary chemo-preventive agents in rat liver: induction of phase I and II drug metabolizing enzymes and aflatoxin B1 metabolism. Carcinogenesis. 1997; 18:1729–1738.

Le HT, Schaldach CM, Firestone GL, et al. Plant-derived 3,3′ Diindolymethane is a strong androgen antagonist in human prostate cancer cells. J Biol Chem. 2003; 278:21136–21145

Carter, T; Liu K, Ralph; Walter, R; DaZhi, C; Mei, Q; Saijun, F; Yuan, F; Rosen, W and Auborn, J. Diindolylmethane alters gene expression in human keratinocytes in vitro. J Nutr. 2002 Nov;132(11):3314-24.

Le HT, Schaldach CM, Firestone GL, Bjeldanes LF. Plant-derived 3,3’-Diindolylmethane is a strong androgen antagonist in human prostate cancer cells. J Biol Chem 2003; 278:21136-45.

Stephensen PU, Bonnesen C, Schaldach C, Andersen O, Bjeldanes LF, Vang O. N-methoxyindole-3-carbinol is a more efficient inducer of cytochrome P-450 1A1 in cultured cells than indol-3-carbinol. Nutr Cancer 2000; 36:112-21.

Bradlow,H.L., Michnovicz,J.J., Telang,N.T. and Osborne,M.P. (1991) Effects of dietary indole-3-carbinol on estradiol metabolism and spontaneous mammary tumors in mice. Carcinogenesis, 12, 1571–1574.

Paraskevaidis A, Drakoulis N, Roots I, Orfanos C, Zouboulis C. Polymorphism in the human cytochrome P-450 1A1 gene (CYP1A1) as a factor for developing acne. Dermatology. 1998;196:171-5.

HeL,YangZ,YuH,ChengB,TangW,DongY,etal.The relationship between CYP17-34T/C polymorphism and acne in Chinese subjects revealed by sequencing. Dermatology. 2006;212:338-42

Marill, J., Cresteil, T., Lanotte, M. et al. Iden- tification of human cytochrome P450s involved in the formation of all-trans-retinoic acid principal metabolites. Mol. Phar- macol. 58, 1341–1348 (2000)