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The bioavailability of sulforaphane from broccoli products in men and its epigenetic activity

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Title: The bioavailability of sulforaphane from broccoli products in men and its epigenetic activity
Author(s): Cramer, Jenna
Advisor(s): Jeffery, Elizabeth H.
Contributor(s): Jeffery, Elizabeth H.; Pan, Yuan-Xiang; Teran-Garcia, Margarita D.
Department / Program: Food Science & Human Nutrition
Discipline: Food Science & Human Nutrition
Degree Granting Institution: University of Illinois at Urbana-Champaign
Degree: Ph.D.
Genre: Doctoral
Subject(s): broccoli sulforaphane cancer histone acetylation DNA methylation Deoxyribonucleic acid (DNA)
Abstract: Epidemiological data show a correlation between broccoli consumption and an anti-cancer benefit. This benefit is attributed to the isothiocyanate sulforaphane (SF). Sulforaphane is derived from the myrosinase-catalyzed hydrolysis of glucoraphanin. Both glucoraphanin and myrosinase are present in fresh or lightly cooked broccoli and broccoli sprouts. Like myrsoinase, gut microflora are capable of hydrolysis of glucoraphanin to SF, although to a much lesser extent than endogenous plant myrosinase (1, 2). It is well established that when glucoraphanin is consumed in the absence of myrosinase, as is the case for heavily cooked broccoli, much of the cancer preventative potential is not availed (1, 3). Similarly, many of the dietary glucoraphanin supplements on the market today lack myrosinase, and may not act as a source of SF. However, the efficacy of these supplements in delivering SF has not been previously evaluated, neither has the potential for restoring the availability of SF by ingesting an exogenous source of myrosinase concomitantly with sources of glucoraphanin that are devoid of endogenous myrosinase. The mechanism of cancer protection by SF is multifaceted, but the best characterized involves the upregulation of detoxification enzymes through the nuclear factor (erythroid-derived 2)-like 2/antioxidant response element pathway (4). More recently, it was discovered that SF also inhibits cancer through epigenetic mechanisms, specifically by decreasing the activities of histone deacetylase and DNA methyltransferase enzymes (5, 6). These effects were most pronounced at 10-15 µM SF, concentrations that are not typically obtained through dietary means. Furthermore, it has not been previously determined whether the inhibition of DNA methyltransferase by SF correlates with increased expression of tumor suppressor genes. The objective of this research was two-fold. First, to determine the plasma and urine levels of SF and metabolites following human ingestion of a glucoraphanin supplement alone or in combination with a myrosinase-rich food source. It was determined that the SF bioavailablity of a high-glucosinolate supplement that was devoid of myrosinase was enhanced by co-consumption with a food source that contained myrosinase. Specifically, plasma total isothiocyanate (ITC) concentration reached 2.86 ± 0.33 µM after the supplement was consumed with fresh broccoli sprouts whereas the peak plasma total ITC concentration after consumption of the glucoraphanin supplement did not reach significance over control meal or baseline values. The second objective was to evaluate the effects on DNA methylation and mRNA expression of cancer-related genes using physiologically attainable concentrations of SF similar to those identified in part one. While the promoters of P16, MGMT and MLH1 were unaffected by SF, DNA methylation at the P21 promoter was decreased by approximately 14% with a concurrent 1.92 ± 0.32 fold increase in mRNA. DNA methylation at the BAX promoter was decreased by a non-significant 11%, but was accompanied by a 1.64 ± 0.09 fold increase in mRNA, which did reach statistical significance. The activity of histone deacetylase and DNA methyltransferase enzymes was also assessed at this physiological concentration of SF. Histone deacetylase activity was unaffected, but DNA methyltransferase activity was decreased to 70.2 ± 9.8% of control after exposure to 5.0 µM SF. These results indicate that the availability of dietary SF can be enhanced by co-consumption of glucoraphanin with an exogenous source of myrosinase. Separately, the results suggest that doses of SF attainable through diet may reduce the risk of cancer development partially by reducing the level of aberrant DNA methylation at the promoters of select tumor suppressor genes. 1. Shapiro TA, Fahey JW, Wade KL, Stephenson KK, Talalay P. Human metabolism and excretion of cancer chemoprotective glucosinolates and isothiocyanates of cruciferous vegetables. Cancer Epidemiol Biomarkers Prev. 1998 Dec;7(12):1091-100. 2. Lai RH, Miller MJ, Jeffery EH. Glucoraphanin hydrolysis by microbiota in the rat cecum results in sulforaphane absorption. Food Funct. 2010;1(2):161-6. 3. Conaway CC, Getahun SM, Liebes LL, Pusateri DJ, Topham DK, Botero-Omary M, Chung FL. Disposition of glucosinolates and sulforaphane in humans after ingestion of steamed and fresh broccoli. Nutr Cancer. 2000;38(2):168-78. 4. Herr I, Buchler MW. Dietary constituents of broccoli and other cruciferous vegetables: Implications for prevention and therapy of cancer. Cancer Treat Rev. 2010 Aug;36(5):377-83. 5. Myzak MC, Karplus PA, Chung FL, Dashwood RH. A novel mechanism of chemoprotection by sulforaphane: Inhibition of histone deacetylase. Cancer Res. 2004 Aug 15;64(16):5767-74. 6. Meeran SM, Patel SN, Tollefsbol TO. Sulforaphane causes epigenetic repression of hTERT expression in human breast cancer cell lines. PLoS One. 2010 Jul 6;5(7):e11457.
Issue Date: 2012-02-01
Genre: thesis
URI: http://hdl.handle.net/2142/29472
Rights Information: Copyright 2011 Jenna Cramer
Date Available in IDEALS: 2012-02-01
2014-02-01
Date Deposited: 2011-12
 

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