Suppressive effects of demethylated metabolites of nobiletin on phorbol ester-induced expression of scavenger receptor genes in THP-1 human monocytic cells

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-κB 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.