Effects of Quinone Derivatives, such as 1,4-Naphthoquinone, on DNA Polymerase Inhibition and Anti-Inflammatory Action

Kazuki      Kobayashi; Shin      Nishiumi; Masayuki      Nishida; Midori      Hirai; Takeshi      Azuma; Hiromi      Yoshida; Yoshiyuki      Mizushina; Masaru      Yoshida

doi:10.2174/157340611794072742

Abstract

Previously, we reported that vitamin K3, which consists of a quinone component, inhibits the activity of human DNA polymerase γ (pol γ). In this study, we investigated the inhibitory effects of 4 quinone derivatives (1,4-benzoquinone (BQ), 1,4-naphthoquinone (NQ), 9,10-anthraquinone (AQ) and 5,12-naphthacenequinone (NCQ)) on the activity of mammalian pols. BQ and NQ potently inhibited the activity of all the pol species: pols α, β, γ, δ, and λ, and NQ was a stronger pol inhibitor than BQ. Because we previously found a positive relationship between pol λ inhibition and antiinflammatory action, we examined whether these quinone derivatives could inhibit inflammatory responses. BQ and NQ caused a marked reduction in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced acute inflammation in mouse ear, although AQ and NCQ did not. In a cell culture system using mouse macrophages, NQ displayed the strongest suppression in the production of tumor necrosis factor (TNF)-α induced by lipopolysaccharide (LPS) among the quinone derivatives tested. Moreover, NQ was found to inhibit the action of nuclear factor (NF)-κB. In an in vivo mouse model of LPSevoked acute inflammation, intraperitoneal injection of BQ and NQ to mice led to suppression of TNF-α production in serum. These anti-inflammatory responses of NQ were more potent than those of BQ. In conclusion, this study has identified several quinone derivatives, such as NQ, that are promising anti-inflammatory candidates.

Keywords: Quinone derivatives, 1,4-naphthoquinone, DNA polymerase, enzyme inhibitor, lipopolysaccharide (LPS), antiinflammation, tumor necrosis factor (TNF), nuclear factor (NF), vitamin K3, 1,4-benzoquinone BQ, 9,10-anthraquinone, 5,12-naphthacenequinone, DNA synthesis, terminal deoxynucleotidyl transferase, eukaryotic pols, reactive oxygen species, 12-O-tetradecanoylphorbol-13-acetate (TPA), fibroblast prolif-eration, granulation, inter-leukin, lipopolysaccharide, Chemically synthesized DNA templates, nucleotides, IgG antibody, Santa Cruz Biotechnology, immuno-affinity column chromatography, distilled dimethyl sulfoxide, EDTA, pentobarbital, Gschwendt's method, American Type Culture Collection, Eagle's Minimum Essential Medium, phosphate buffered saline, enzyme-linked immu-nosorbent assay, protease inhibitors, phosphatase inhibitors, bicinchoninic acid, Tris-buffered saline TBS-T, anti-actin antibody, intraperitoneally injected, representative replicative pol, re-pair/recombination-related pols, mitochondrial pols, edema, Peritoneal Macrophages, inflammatory cytokine, dose-response curves, novel thera-peutic agents, base exci-sion repair (BER), normal hyper-mutation pattern, novel anti-inflammatory compounds, chemopreventive agent