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(median effect
plot|tert-butylhydroperoxide|peroxynitrite| glutathione|quinone
reductase|4-hydroxynonenal)
Lewis B. and Dorothy Cullman Cancer Chemoprotection Center, and
Department of Pharmacology and Molecular Sciences, The Johns Hopkins
University School of Medicine, Baltimore, MD 21205
Contributed by Paul Talalay, October 26, 2001
Mammalian cells are equipped with elaborate systems
for protection against the toxicity of reactive oxygen and nitrogen
species and electrophiles that are constant dangers to the integrity
of their DNA. Phase 2 enzymes (e.g., glutathione
transferases, NAD(P)H:quinone reductase) and glutathione synthesis are
widely recognized as playing major protective roles against
electrophilic carcinogens, but their antioxidant functions have
attracted far less attention. The cytotoxicities of four oxidative
stressors (menadione, tert-butyl hydroperoxide,
4-hydroxynonenal, and peroxynitrite) for human adult retinal pigment
epithelial cells (ARPE-19) were quantified by measuring the
concentration dependence of cell death and were expressed as the median
effect dose (Dm) for each oxidant. After treatment of ARPE-19 cells for 24 h with 0-5 µM concentrations of sulforaphane (the powerful Phase 2 enzyme inducer isolated from
broccoli), the toxicities of the oxidants were markedly reduced as
shown by 1.5- to 3-fold increases in Dm
values. The magnitude of protection was a function of the nature of the
oxidants and the concentrations of both the oxidants and sulforaphane.
Protection was prolonged and persisted for several days after removal
of sulforaphane before returning to control levels. The
sulforaphane-dependent increases in specific activities of cytosolic
quinone reductase and the glutathione levels were highly significantly
correlated with the degree of protection as measured by
Dm values. Antioxidant protection was also
demonstrated for human HaCaT keratinocytes and L1210 murine leukemia
cells. It is therefore highly likely that the multifaceted and
prolonged antioxidant protection provided by sulforaphane is a general
phenomenon that is mediated through induction of the Phase 2 enzyme response.
Medical Sciences
Powerful and prolonged protection of human retinal pigment
epithelial cells, keratinocytes, and mouse leukemia cells against
oxidative damage: The indirect antioxidant effects of sulforaphane
*
To whom reprint requests should be addressed. E-mail:
ptalalay{at}jhmi.edu.
www.pnas.org/cgi/doi/10.1073/pnas.261572998
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