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.
Carbonyl reduction is a significant step in the phase I biotransformation 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-beta. In the present study, the metabolic fate and possible involvement of 11beta-hydroxysteroid dehydrogenase (11beta-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 beta-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, 18beta-glycyrrhetinic acid, a selective inhibitor of 11beta-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.
Doping Control Center, Korea Institute of Science and Technology, Seoul, Korea.
Sang Kyu
SK
Lee
Ju Hyun
JH
Kim
Young Min
YM
Seo
Hye Chun Hwa
HC
Kim
Mi Jeong
MJ
Kang
Hye Gwang
HG
Jeong
Eung Seok
ES
Lee
Tae Cheon
TC
Jeong
D042842:11-beta-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism*; D001711:Biotransformation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005663:Furans / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D009249:NADP / Q000378:metabolism; D011407:Propane / Q000031:analogs & derivatives* / Q000378:metabolism; D011725:Pyridines / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
C508534:1-furan-2-yl-3-pyridin-2-yl-propenone; D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D005663:Furans; D011725:Pyridines; D009249:NADP; D000429:Alcohol Oxidoreductases; D042842:11-beta-Hydroxysteroid Dehydrogenases; D011407:Propane