Coordinate regulation of enzyme markers for inflammation and for protection against oxidants and electrophiles.
An elaborate network of highly inducible phase 2 proteins protects aerobic cells against the cumulative damaging effects of reactive oxygen intermediates and toxic electrophiles, which are the major causes of malignancy and chronic degenerative diseases. Many chemical and phytochemical agents, all of which react with thiol groups, induce the phase 2 response through their reactivity with critical cysteine thiols of Keap1. We recently found that the anti-inflammatory potencies (suppression of iNOS and COX-2 expression) of a series of triterpenoids with Michael reaction centers were closely correlated with the potencies of these agents to induce the phase 2 response. We now report that representatives of seven recognized chemical classes of inducers, including isothiocyanates, bisbenzylidenes, arsenicals, heavy metals, and vicinal dithiols, showed highly correlated inducer and anti-inflammatory potencies spanning more than six orders of magnitude of concentrations in established cells and in primary mouse peritoneal macrophages. Potency measurements were expressed as the D(m) values (median effect concentration) by use of the Median Effect Equation. Whereas the phase 2 induction required the functional integrity of both the repressor Keap1 and the transcription factor Nrf2, the effectiveness of inducers in blocking the up-regulation of iNOS by inflammatory cytokines was related to the nature of the cytokine and the inducer concentration. These studies identify suppression of inflammation as a consistent property of inducers of the phase 2 response and strongly suggest that this property is a central aspect of their chemoprotective actions.
Lewis B. and Dorothy Cullman Cancer Chemoprotection Center, Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Hua
H
Liu
Albena T
AT
Dinkova-Kostova
Paul
P
Talalay
D000209:Acute-Phase Proteins; D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D000818:Animals; D001152:Arsenicals; D001597:Benzylidene Compounds; D015415:Biomarkers; D003598:Cytoskeletal Proteins / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D015386:Hazardous Substances / Q000037:antagonists & inhibitors*; D007249:Inflammation / Q000188:drug therapy* / Q000201:enzymology; D017879:Isothiocyanates; D000072019:Kelch-Like ECH-Associated Protein 1; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D019216:Metals, Heavy; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000502:physiology; D016877:Oxidants / Q000037:antagonists & inhibitors*; D020011:Protective Agents / Q000494:pharmacology*; D014050:Toluene / Q000031:analogs & derivatives
D000209:Acute-Phase Proteins; D048868:Adaptor Proteins, Signal Transducing; D001152:Arsenicals; D001597:Benzylidene Compounds; D015415:Biomarkers; D003598:Cytoskeletal Proteins; D015386:Hazardous Substances; D017879:Isothiocyanates; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D019216:Metals, Heavy; D051267:NF-E2-Related Factor 2; D016877:Oxidants; D020011:Protective Agents; D014050:Toluene; C004848:dithiol