THE SULFORAPHANES AND PHASE 2 ENZYME INDUCTION
Paul Talalay
Brassica Cancer Chemoprotection Laboratory, Department of Pharmacology
and Molecular Sciences, Johns Hopkins University School of Medicine,
Baltimore, MD 21205
Multiple lines of evidence link oxidative damage with rates of aging
and age-related chronic diseases such as cancer, but the ability to
modulate these processes by administration of conventional and
naturally occurring direct antioxidants is not persuasive. The
transcriptional activation of Phase 2 genes (e.g., coding for
glutathione transferases, NAD(P)H:quinone reductase,
glucuronosyltransferases, heme oxygenase 1, etc.) and those involved in
glutathione synthesis are emerging as major strategies for protection
of cells against the damaging effects of both oxidants and
electrophiles, including neoplastic transformations. The activation of
Phase 2 genes results in versatile, long-lasting antioxidant
protection. This indirect antioxidant protection is catalytic, unlike
direct antioxidants which are consumed in radical scavenging processes.
Fortunately many edible plants, some of which are eaten in substantial
quantities, contain potent phytochemical inducers of the Phase 2
response, and can inhibit carcinogenesis in animal models. It is
tempting to attribute the rather special protective qualities of
cruciferous vegetables to their high content of such inducers.
Sulforaphane, an isothiocyanate isolated from broccoli and other
crucifers (existing in the intact plant as its glucosinolate precursor)
is a very potent Phase 2 inducer. The molecular mechanism of induction
involves covalent interaction of inducers with certain specific
cysteine thiols of Keap1 which is a protein anchored in the cytoplasm
to the actin cytoskeleton. Keap1 is a multidomain protein that normally
binds powerfully to the transcription factor Nrf2, thereby retaining
Nrf2 in the cytoplasm. Upon modification by inducers, Keap1 undergoes
conformational changes, releases Nrf2 which migrates to the nucleus
where it binds to the AREs (Antioxidant Response Elements) of Phase 2
genes and (in dimeric combination with other factors) activates the
transcription of these genes. The resultant elevation of the Phase 2
response protects mammalian cells against the toxicities of
electrophiles and oxidants. Evaluations in multiple animal models and
high risk populations are in progress (Supported by NIH Grants CA
94076, CA 93780, American Institute for Cancer Research,and the Lewis
B. and Dorothy Cullman Foundation).
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