Extremely potent triterpenoid inducers of the phase 2 response: correlations of protection against oxidant and inflammatory stress.

Abstract

A series of synthetic triterpenoid (TP) analogues of oleanolic acid are powerful inhibitors of cellular inflammatory processes such as the induction by IFN-gamma 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 NAD(P)H-quinone oxidoreductase in murine hepatoma cells at 0.28 nM and has an IC(50) 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 (r(2) = 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.

• Authors: Albena T Dinkova-Kostova, Karen T Liby, Katherine K Stephenson, W David Holtzclaw, Xiangqun Gao, Nanjoo Suh, Charlotte Williams, Renee Risingsong, Tadashi Honda, Gordon W Gribble, Michael B Sporn, Paul Talalay
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 102 Issue 12 Pg. 4584-9 (Mar 22 2005) ISSN: 0027-8424 [Print] United States
• PMID: 15767573 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Adaptor Proteins, Signal Transducing
• Cytoskeletal Proteins
• DNA-Binding Proteins
• Enzyme Inhibitors
• Keap1 protein, mouse
• Kelch-Like ECH-Associated Protein 1
• NF-E2-Related Factor 2
• NFE2L2 protein, human
• Nfe2l2 protein, mouse
• RNA, Messenger
• Terpenes
• Trans-Activators
• NOS2 protein, human
• Nitric Oxide Synthase
• Nitric Oxide Synthase Type II
• Nos2 protein, mouse
• NAD(P)H Dehydrogenase (Quinone)
• Nqo1 protein, mouse
• NADPH Dehydrogenase

Topics

• Adaptor Proteins, Signal Transducing (metabolism)
• Animals
• Binding, Competitive
• Cell Line
• Cytoskeletal Proteins (metabolism)
• DNA-Binding Proteins (metabolism)
• Enzyme Induction (drug effects)
• Enzyme Inhibitors (chemistry, pharmacology)
• Humans
• Inflammation (prevention & control)
• Kelch-Like ECH-Associated Protein 1
• Mice
• NAD(P)H Dehydrogenase (Quinone)
• NADPH Dehydrogenase (antagonists & inhibitors, biosynthesis)
• NF-E2-Related Factor 2
• Nitric Oxide Synthase (antagonists & inhibitors, biosynthesis, genetics)
• Nitric Oxide Synthase Type II
• Oxidative Stress (drug effects)
• RNA, Messenger (genetics, metabolism)
• Structure-Activity Relationship
• Terpenes (chemistry, pharmacology)
• Trans-Activators (metabolism)
• U937 Cells