title: Suppressive effects of demethylated metabolites of nobiletin on phorbol ester-induced expression of scavenger receptor genes in THP-1 human monocytic cells.
abstract: Unregulated uptake of oxidized low-density lipoproteins (ox-LDL) via macrophage scavenger receptors (SRs) is a key event in atherosclerosis. We previously reported that nobiletin (NOB), a citrus polymethoxylated flavone, markedly reduced 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced SRs and adhesion molecules mRNA expression and blockade of DiI-acLDL uptake in THP-1 human monocyte-like cells. In this study, we examined the effects of NOB metabolites, 3'-hydroxy-5,6,7,8,4'-pentamethoxyflavone (3'-demethyl-NOB), 4'-hydroxy-5,6,7,8,3'-pentamethoxyflavone (4'-demethyl-NOB) and 3', 4'-dihydroxy-5,6,7,8,-tetramethoxyflavone (3', 4'-didemethyl-NOB) and NOB analog, tangeretin, on SRs and adhesion molecules mRNA expression. 3'-Demethyl-NOB significantly suppressed CD36 expression, moreover, 4'-demethyl- and 3', 4'-didemethyl-NOB significantly suppressed TPA-induced expression of SR-A and LOX-1. Further, the suppressive effects of 4'-demethyl- and 3', 4'-didemethyl-NOB on the expression of CD36 mRNA were greater extent than parent NOB. The inhibitory effects of the metabolites toward TPA-induced SR mRNA expression are partly associated with the suppression of AP-1 and NF-kappaB transcriptional activities. Together, our results suggest that metabolites of NOB, such as 4'-demethyl- and 3', 4'-didemethyl-NOB, have comparable or higher potentials to attenuate SR expression than NOB.
authors.affiliation: Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan.
authors.forename: Ai
authors.initials: A
authors.lastname: Eguchi
authors.forename: Akira
authors.initials: A
authors.lastname: Murakami
authors.forename: Shiming
authors.initials: S
authors.lastname: Li
authors.forename: Chi-Tang
authors.initials: CT
authors.lastname: Ho
authors.forename: Hajime
authors.initials: H
authors.lastname: Ohigashi
mesh_terms: D018955:CD36 Antigens / Q000096:biosynthesis; D002460:Cell Line; D015536:Down-Regulation; D047309:Flavones / Q000378:metabolism* / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051116:Receptors, Scavenger / Q000096:biosynthesis* / Q000235:genetics; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: C515880:3'-demethylnobiletin; C515881:4'-demethylnobiletin; D018955:CD36 Antigens; D047309:Flavones; D016328:NF-kappa B; D012333:RNA, Messenger; D051116:Receptors, Scavenger; D018808:Transcription Factor AP-1; C008661:nobiletin; C059006:tangeretin; D013755:Tetradecanoylphorbol Acetate