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KMID : 0043320080310060764
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Archives of Pharmacal Research
2008 Volume.31 No. 6 p.764 ~ p.770
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In vitro Characterization of the Enzymes Involved in the Metabolism of 1-furan-2-yl-3-pyridin-2-yl-propenone, an Anti-inflammatory Propenone Compound
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Lee Sang-Kyu
Kim Ju-Hyun
Seo Young-Min
Kim Hye-Chun-Hwa
Kang Mi-Jeong
Jeong Hye-Gwang
Lee Eung-Seok
Jeong Tae-Cheon
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Abstract
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Carbonyl reduction is a significant step in the phase I biotrans formation of a great variety of aromatic, alicyclic and aliphatic carbonyl compounds. 1-Furan-2-yl-3-pyridin-2-yl-propenone (FPP-3) has been shown to have anti-inflammatory activity as it inhibits the production of nitric oxide and tumor necrosis factor-. In the present study, the metabolic fate and possible involvement of -hydroxysteroid dehydrogenase (-HSD) and carbonyl reductase (CBR) in the metabolism of FPP-3 were investigated in rat liver subcellular fractions. When FPP-3 was incubated with rat liver subcellular fractions in the presence of -NADPH, two major peaks were detected by reduction on the propenone: M1 (1-furan-2-yl-3-pyridin-2-yl-propan-1-one) and M2 (1-furan-2-yl-3-pyridin-2-yl-propan-1-ol). Inhibitors of CBR, such as quercitrin, ethacrynic acid and menadione, significantly increased the formation of M1, but effectively inhibited the formation of M2 in subcellular fractions. Meanwhile, -glycyrrhetinic acid, a selective inhibitor of -HSD, marginally inhibited the reduction of FPP-3 in microsomes. A good correlation was observed between the formation of M2 and CBR activity with either 4-pyridine carboxaldehyde (r=0.72) or D,L-glyceraldehyde (r=0.63) as substrates in the cytosol. These results indicated that FPP-3 might be metabolized by cytosolic CBR and uncharacterized microsomal reductase(s) in rat liver.
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KEYWORD
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FPP-3, Carbonyl reductase, Metabolism, LC-ESI/MS, In vitro, Phase I
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