The effectiveness of the isothiocyanate sulforaphane in chemoprotection
Research output: Chapter in Book/Report/Conference proceeding › Conference contribution
|Place of publication||Lillehammer, Norway|
|Publisher||International Society for Horticultural Science |
|Number of pages||10|
|Conference||Proceedings of the Fifth International Symposium on Brassicas and the Sixteenth International Crucifer Genetics Workshop, Brassica 2008|
|Period||8/09/08 → 12/09/08|
In addition to their nutritional value, edible plants are recognized as a primary and rich source of biologically active natural products. Many are capable of transcriptionally upregulating (inducing) mammalian cytoprotective enzymes. Some of the most potent naturally occurring inducers are isothiocyanates that are derived from glucosinolate precursors by the action of ß-thioglucosidase enzymes (myrosinases). The isothiocyanate sulforaphane was isolated from extracts of broccoli (Brassica oleracea) as the principal inducer of NAD(P)H:quinone oxidoreductase 1 (NQO1), a marker cytoprotective enzyme. Sulforaphane activates transcription of cytoprotective genes via the Keap1/Nrf2/ARE pathway by chemically modifying highly reactive cysteine residues of Keap1, the cellular sensor for inducers. As a consequence, Keap1 loses its ability to target transcription factor Nrf2 for ubiquitination and proteasomal degradation, resulting in its stabilization and nuclear translocation where (as a heterodimer with a small Maf protein), it binds to the antioxidant response element (ARE) and activates transcription of cytoprotective genes. Global gene expression profiling has confirmed that exposure to sulforaphane results in Nrf2-dependent upregulation of cytoprotective genes such as NQO1, UDP-glucuronosyltransferase, heme oxygenase 1, ?-glutamatecysteine ligase, epoxide hydrolase, thioredoxin reductase 1, and multidrug resistant protein. Furthermore, the protective effects of sulforaphane against toxicity and carcinogenicity have been demonstrated in various animal models. In addition to potently activating the Keap1/Nrf2/ARE pathway, sulforaphane inhibits pro-inflammatory responses (i.e., lipopolysaccharide- and interferon-?- mediated elevation of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2)). Topical daily applications of a standardized broccoli extract (delivering ~100 nmol/cm 2 sulforaphane) to mice at high risk for skin tumor development leads to ~50% reduction in tumor incidence, multiplicity, and volume. In humans, topical applications of broccoli extracts induce cytoprotective enzymes and protect against photodamage. Because the effects of sulforaphane are due to enhancement of the biosynthesis of cytoprotective proteins and inhibition of inflammatory processes, the protection is comprehensive and long-lasting.