TY - GEN
T1 - The effectiveness of the isothiocyanate sulforaphane in chemoprotection
AU - Dinkova-Kostova, A. T.
PY - 2010/6/30
Y1 - 2010/6/30
N2 - 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 β-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, γ-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-γ- mediated elevation of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2)). Topical daily applications of a standardized broccoli extract (delivering ∼100 nmol/cm2 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.
AB - 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 β-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, γ-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-γ- mediated elevation of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2)). Topical daily applications of a standardized broccoli extract (delivering ∼100 nmol/cm2 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.
KW - Inflammation
KW - Keap1
KW - NQO1
KW - Nrf2
KW - Phase 2 enzyme
KW - Photoprotection
UR - http://www.scopus.com/inward/record.url?scp=77957126067&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77957126067&partnerID=8YFLogxK
M3 - Conference contribution
AN - SCOPUS:77957126067
SN - 9789066054301
VL - 867
T3 - Acta Horticulturae
SP - 27
EP - 36
BT - Acta Horticulturae
ER -