chapter  8
24 Pages

The Isothiocyanate Sulforaphane Induces the Phase 2 Response by Signaling of the Keap1–Nrf2–ARE Pathway: Implications for Dietary Protection against Cancer

Biological Phenomenon ........................................................................... 209 8.4 Sulforaphane, a Potent Inducer of the Phase 2 Response ........................ 212 8.5 Molecular Mechanism of Induction of the Phase 2 Response ................. 214 8.6 Sulforaphane Inhibits Tumor Development in Animal Models ............... 215 8.7 Sulforaphane Metabolism ........................................................................ 218 Acknowledgments ............................................................................................. 221 Abbreviations .................................................................................................... 221 References ......................................................................................................... 222

In the course of evolution, all eukaryotes have developed sophisticated defense systems that allow their survival and coevolution with other competing organisms. These include the biosynthesis of a wide array of small molecules (secondary metabolites) with extraordinarily sophisticated chemistry in plants, as well as elaborate enzymatic systems capable of coping with the toxicities of electrophiles and oxidants (phase 2 enzymes) in both plants and animals. Phase 2 enzymes catalyze enormously versatile chemical reactions that collectively lead to detoxifi cation of various electrophiles and oxidants. Together with housekeeping antioxidant enzymes (e.g., catalase, superoxide dismutase) and small molecular mass direct antioxidants (e.g, ascorbic acid, tocopherol, glutathione), phase 2 enzymes constitute an integral part of the cellular defense. Furthermore, the discoveries that (1) phase 2 enzymes can be induced selectively (without concomitant induction of phase 1 enzymes) by a wide variety of stimuli that we now simply call “inducers” and (2) this “induced state” that we now refer to as “the phase 2 response” could explain how so many diverse chemical agents could block carcinogenesis in various animal models led to the birth of the hypothesis that induction of phase 2 enzymes could be a powerful strategy for protection against cancer and other chronic diseases [1-3].