SY33-03

Many epidemiological studies spanning some 20 years have demonstrated an inverse quantitative relation between the consumption of plant-based diets and the risk of developing a variety of cancers and a number of chronic degenerative diseases, including atherosclerosis. More recent refinements of these investigations have revealed the singular protective properties (in particular against mammary, colorectal, and bladder cancers) of one family of plants: Crucifers, which are widely consumed in many regions of the world. There is substantial evidence that the very high concentrations of glucosinolates (GS), secondary phytochemicals present in the seeds, sprouts, and mature forms of Brassicaceae (also known as Cruciferae) play a major role in these protective effects. More than 120 GS have been isolated from plants. GS are β-thioglucoside N-hydroxysulfates with aliphatic, aromatic, or indole sidechains. They are biosynthesized by plants from common amino acids by a unique series of reactions. Many of the effects of GS on animal tissues are almost certainly not due to the GS themselves but to their isothiocyanate (ITC) and other enzymatic hydrolysis products.
 Conversion of Glucosinolates to Isothiocyanates: Bioactivation and Bioavailability. The conversion of GS to ITC is promoted by plant myrosinases that coexist but are physically segregated from their GS substrates in plant cells, and are released when plant cells are crushed (e.g., chewing). This conversion is also carried out by the microflora of the human gastrointestinal tract. Thus, treatment of human volunteers with oral antibiotics and mechanical bowel cleansing completely and reversibly abolished this conversion. Interestingly, the efficiency of the GS to ITC conversion varies enormously among individuals (from as little as 2% to as much as 40% in one of our studies), but tended to be quite constant over time in single individuals. Since the efficiency of conversion may limit protective efficacy, differences in bioavailability of ITC from GS among individuals may have important long-term health implications.
 Protection of Skin against UV Radiation by Sulforaphane (SF) . Isolation from broccoli of the ITC sulforaphane, as the hydrolysis product of its GS precursor glucoraphanin, has played a major role in demonstrating the importance of the transcriptional upregulation of the cellular phase 2 response as a protective strategy. SF is one of the most potent naturally-occurring inducers of a family of cytoprotective genes that defend cells against the damaging effects of electrophiles, oxidants, inflammation, and radiation. These genes are controlled by the Keap1/Nrf2/ARE signaling pathway. SF protects the skin of SKH-1 hairless mice against UV-evoked tumors, and reduces UV erythema in human skin.
 Antibiotic Activities of Isothiocyanates. Based on anecdotal reports that broccoli sprout consumption relieved peptic ulcer symptoms, we made the serendipitous observation that SF is a very potent and highly selective antibiotic against Helicobacter pylori. SF is bacteriostatic against many clinical isolates of H. pylori including those that are resistant to conventional antibiotics. SF eliminated intracellular helicobacter infections from a human epithelial cell line, blocked formation of benzo[a]pyrene-evoked forestomach tumors in mice, provided that the nrf2 gene was intact. SF also eliminated H. pylori from gastric xenografts in nude mice. Furthermore, SF dramatically reduced the inflammation of stomachs in mice challenged with a salt-induced gastritis. These effects were much less marked in nrf2 negative mice. Since H. pylori infections have been strongly implicated in the etiology of gastric cancer in humans, the triple actions of SF in mice: suppressing H. pylori colonization of the stomach, inhibiting the associated inflammatory processes, and blocking gastric carcinogenesis, offer promise for diet-based protection of humans against gastric cancer.

99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA