TY - JOUR
T1 - Extremely potent triterpenoid inducers of the phase 2 response
T2 - Correlations of protection against oxidant and inflammatory stress
AU - Dinkova-Kostova, Albena T.
AU - Liby, Karen T.
AU - Stephenson, Katherine K.
AU - Holtzclaw, W. David
AU - Gao, Xiangqun
AU - Suh, Nanjoo
AU - Williams, Charlotte
AU - Risingsong, Renee
AU - Honda, Tadashi
AU - Gribble, Gordon W.
AU - Sporn, Michael B.
AU - Talalay, Paul
PY - 2005/3/22
Y1 - 2005/3/22
N2 - A series of synthetic triterpenoid (TP) analogues of oleanolic acid are powerful inhibitors of cellular inflammatory processes such as the induction by IFN-γ of inducible nitric oxide synthase (iNOS) and of cyclooxygenase 2 in mouse macrophages. Here, we show that these analogues are also extremely potent inducers of the phase 2 response [e.g., elevation of NAD(P)H-quinone oxidoreductase and heme oxygenase 1], which is a major protector of cells against oxidative and electrophile stress. Moreover, like previously identified phase 2 inducers, the TP analogues use the antioxidant response element-Nrf2-Keap1 signaling pathway. Thus, induction of the phase 2 response and suppression of the iNOS induction was abrogated in nrf2-/- and keap1-/- mouse embryonic fibroblasts. The high potency of TP analogues in inducing the phase 2 response and blocking inflammation depends on the presence of activated Michael reaction (enone) functions at critical positions in rings A and C. The most potent TP doubles MAD(P)H-quinone oxidoreductase in murine hepatoma cells at 0.28 nM and has an IC50 for suppression of iNOS induction in primary mouse macrophages of 0.0035 nM. The direct interaction of this TP with thiol groups of the Keap1 sensor for inducers is demonstrated spectroscopically. The antiinflammatory and phase 2 inducer potencies of 18 TP are closely linearly correlated (r2 = 0.91) over 6 orders of magnitude of concentration. Thus, in addition to blocking inflammation and promoting differentiation, these TP exhibit another very important protective property: the induction of the phase 2 response.
AB - A series of synthetic triterpenoid (TP) analogues of oleanolic acid are powerful inhibitors of cellular inflammatory processes such as the induction by IFN-γ of inducible nitric oxide synthase (iNOS) and of cyclooxygenase 2 in mouse macrophages. Here, we show that these analogues are also extremely potent inducers of the phase 2 response [e.g., elevation of NAD(P)H-quinone oxidoreductase and heme oxygenase 1], which is a major protector of cells against oxidative and electrophile stress. Moreover, like previously identified phase 2 inducers, the TP analogues use the antioxidant response element-Nrf2-Keap1 signaling pathway. Thus, induction of the phase 2 response and suppression of the iNOS induction was abrogated in nrf2-/- and keap1-/- mouse embryonic fibroblasts. The high potency of TP analogues in inducing the phase 2 response and blocking inflammation depends on the presence of activated Michael reaction (enone) functions at critical positions in rings A and C. The most potent TP doubles MAD(P)H-quinone oxidoreductase in murine hepatoma cells at 0.28 nM and has an IC50 for suppression of iNOS induction in primary mouse macrophages of 0.0035 nM. The direct interaction of this TP with thiol groups of the Keap1 sensor for inducers is demonstrated spectroscopically. The antiinflammatory and phase 2 inducer potencies of 18 TP are closely linearly correlated (r2 = 0.91) over 6 orders of magnitude of concentration. Thus, in addition to blocking inflammation and promoting differentiation, these TP exhibit another very important protective property: the induction of the phase 2 response.
KW - Inflammation
KW - NAD(P)H-quinone acceptor oxidoreductase
KW - Nrf2 Keap1
KW - Oxidative stress
KW - Phase 2 enzymes
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U2 - 10.1073/pnas.0500815102
DO - 10.1073/pnas.0500815102
M3 - Article
C2 - 15767573
AN - SCOPUS:20144383831
SN - 0027-8424
VL - 102
SP - 4584
EP - 4589
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 12
ER -