| RRC ID |
67915
|
| 著者 |
Yamazaki Y, Yasuda K, Matsuyama T, Ishihara T, Higa R, Sawairi T, Yamaguchi M, Egi M, Akai S, Miyase T, Ikari A, Miwa M, Sugatani J.
|
| タイトル |
A Penicillium sp. F33 metabolite and its synthetic derivatives inhibit acetyl-CoA:1-O-alkyl-sn-glycero-3-phosphocholine acetyltransferase (a key enzyme in platelet-activating factor biosynthesis) and carrageenan-induced paw edema in mice.
|
| ジャーナル |
Biochem Pharmacol
|
| Abstract |
Acetyl-CoA:1-O-alkyl-sn-glycero-3-phosphocholine (lyso-PAF) acetyltransferase is a key enzyme in the biosynthesis of 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (PAF) in inflammatory cells. Substances which inhibit this enzyme are of therapeutic interest. In this study, we screened for new inhibitors of lyso-PAF acetyltransferase with anti-inflammatory effects. In a metabolite from Penicillium sp. F33, we isolated an acetyltransferase inhibitor identified as dihydrofumigatin (2-methoxy-1,3,4-trihydroxy-5-methylbenzene) from high resolution mass spectrometer and NMR data. Dihydrofumigatin had strong acetyltransferase inhibitory activity, but was not stable in aqueous solution. Thus, we chemically synthesized its oxidized form fumigatin (3-hydroxy-2-methoxy-5-methyl-1,4-benzoquinone) and derivatives thereof, and evaluated their inhibitory effects. Strong inhibitory activity was observed for saturated fatty acid esters of fumigatin; the order of inhibition was 3-decanoyloxy-2-methoxy-5-methyl-1,4-benzoquinone (termed FUD-7, IC₅₀ = 3 μM)>2-methoxy-5-methyl-3-tetradecanoyloxy-1,4-benzoquinone (termed FUD-8, IC₅₀ = 20 μM)>3-hexanoyloxy-2-methoxy-5-methyl-1,4-benzoquinone (IC₅₀ = 139 μM). Interestingly, these compounds also significantly suppressed the gene expression of lyso-PAF acetyltransferase/LPCAT2 in mouse bone marrow-derived macrophages stimulated by lipopolysaccharide (LPS). We further evaluated the effect of these substances on anti-inflammatory activity in vivo using the carrageenan-induced mouse paw edema test. FUD-7 and FUD-8 at 2.5 mg/kg showed significant, 47.9-51.7%, inhibition stronger than that of prednisolone at 10 mg/kg (41.9%). These results suggest that FUD-7 and FUD-8 are potent inhibitors with anti-inflammatory activity.
|
| 巻・号 |
86(5)
|
| ページ |
632-44
|
| 公開日 |
2013-9-1
|
| DOI |
10.1016/j.bcp.2013.06.021
|
| PII |
S0006-2952(13)00392-4
|
| PMID |
23817078
|
| MeSH |
Acetyltransferases / antagonists & inhibitors*
Animals
Base Sequence
Benzoquinones / pharmacology
Carrageenan / toxicity*
Cells, Cultured
Cyclohexanones / pharmacology
DNA Primers
Edema / chemically induced
Edema / enzymology*
Male
Mice
Mice, Inbred C57BL
Penicillium / metabolism*
Platelet Activating Factor / biosynthesis*
Rats
Rats, Wistar
Real-Time Polymerase Chain Reaction
|
| IF |
4.96
|
| リソース情報 |
| ヒト・動物細胞 |
L929 |
