title: Caffeic acid phenethyl ester activation of Nrf2 pathway is enhanced under oxidative state: structural analysis and potential as a pathologically targeted therapeutic agent in treatment of colonic inflammation.
abstract: Caffeic acid phenethyl ester (CAPE) is a polyphenolic natural product that possesses numerous biological activities including anti-inflammatory effects. CAPE-mediated nuclear factor-erythroid 2 p45 (NF-E2)-related factor 2 (Nrf2) activation is likely responsible for some of its biological effects. CAPE was chemically modified to yield CAPE analogues that were subjected to experiments examining cellular Nrf2 activity. CAPE and the CAPE analogue with a catechol moiety, but not the other analogues, activated the Nrf2 pathway. In addition, only biotin-labeled CAPE analogues with the catechol moiety precipitated Kelch-like ECH associated protein 1 (Keap1) when incubated with cell lysates and streptavidin agarose beads. Sodium hypochlorite (NaOCl) oxidation of the catechol moiety in CAPE produced an oxidized, electrophilic form of CAPE (Oxi-CAPE) and greatly enhanced the ability of CAPE to activate Nrf2 and to bind to Keap1. Rectal administration of CAPE ameliorated 2,4,6-trinitrobenzene sulfonic acid-induced rat colitis and activated the Nrf2 pathway in the inflamed colon, and incubation of CAPE in the lumen of the inflamed distal colon generated Oxi-CAPE. However, these biological effects and chemical change of CAPE were not observed in the normal colon. Our data suggest that CAPE requires the catechol moiety for the oxidation-enhanced activation of the Nrf2 pathway and has potential as a pathologically targeted Nrf2-activating agent that is exclusively activated in pathological states with oxidative stress such as colonic inflammation.
authors.affiliation: College of Pharmacy, Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Hyunjeong
authors.initials: H
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Wooseong
authors.initials: W
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Soohwan
authors.initials: S
authors.lastname: Yum
authors.affiliation: College of Pharmacy, Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Sungchae
authors.initials: S
authors.lastname: Hong
authors.affiliation: Department of Civil and Environmental Engineering, Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Jeong-Eun
authors.initials: JE
authors.lastname: Oh
authors.affiliation: Department of Civil and Environmental Engineering, Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Ji-Woo
authors.initials: JW
authors.lastname: Lee
authors.affiliation: College of Pharmacy, The Catholic University of Korea, Bucheon, Gyeonggi-do 420-743, Republic of Korea.
authors.forename: Mi-Kyoung
authors.initials: MK
authors.lastname: Kwak
authors.affiliation: College of Pharmacy, Kyungpook National University, Daegu, 702-701, Republic of Korea.
authors.forename: Eun Ji
authors.initials: EJ
authors.lastname: Park
authors.affiliation: College of Pharmacy, Kyungpook National University, Daegu, 702-701, Republic of Korea.
authors.forename: Dong Hee
authors.initials: DH
authors.lastname: Na
authors.affiliation: College of Pharmacy, Pusan National University, Busan 609-735, Republic of Korea. Electronic address: jungy@pusan.ac.kr.
authors.forename: Yunjin
authors.initials: Y
authors.lastname: Jung
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D002109:Caffeic Acids / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D003092:Colitis / Q000378:metabolism*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D047468:Immunoprecipitation; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000893:Anti-Inflammatory Agents; D002109:Caffeic Acids; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol
keywords: 2,4,6-Trinitrobenzene sulfonic acid; 3-phenylpropionic acid phenethyl ester; ARE; Antioxidant response element; BTCA; BTDHHC; BTDMC; Biotin-tagged caffeic acid; Biotin-tagged dihydroxydihydrocinnamic acid; Biotin-tagged dimethoxycinnamic acid; CAPE; Caffeic acid phenethyl ester; DHHC; DMC; DMHC; Dihydrohydroxycinnamic acid phenethyl ester; Dimethoxycinnamic acid phenethyl ester; Dimethoxydihydrocinnamic acid phenethyl ester; Electrophile; HBSS; Hank′s buffered salt solution; Keap1; Kelch-like ECH associated protein 1; MPO; Nrf2; Nuclear factor-erythroid 2 p45 (NF-E2)-related factor 2; Oxidation of catechol; PPAPE; Pathologically targeted therapeutic agent; Structural analysis; TNBS; myeloperoxidase