Phytoestrogens as inhibitors of the human progesterone metabolizing enzyme AKR1C1.
Phytoestrogens are plant-derived, non-steroidal constituents of our diets. They can act as agonists or antagonists of estrogen receptors, and they can modulate the activities of the key enzymes in estrogen biosynthesis. Much less is known about their actions on the androgen and progesterone metabolizing enzymes. We have examined the inhibitory action of phytoestrogens on the key human progesterone-metabolizing enzyme, 20alpha-hydroxysteroid dehydrogenase (AKR1C1). This enzyme inactivates progesterone and the neuroactive 3alpha,5alpha-tetrahydroprogesterone, to form their less active counterparts, 20alpha-hydroxyprogesterone and 5alpha-pregnane-3alpha,20alpha-diol, respectively. We overexpressed recombinant human AKR1C1 in Escherichia coli, purified it to homogeneity, and examined the selected phytoestrogens as inhibitors of NADPH-dependent reduction of a common AKR substrate, 9,10-phenantrenequinone, and progesterone. The most potent inhibitors were 7-hydroxyflavone, 3,7-dihydroxyflavone and flavanone naringenin with IC(50) values in the low microM range. Docking of the flavones in the active site of AKR1C1 revealed their possible binding modes, in which they are sandwiched between the Leu308 and Trp227 of AKR1C1.
Brozic
Petra
P
Institute of Biochemistry, Medical Faculty, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia.
Smuc
Tina
T
Gobec
Stanislav
S
Rizner
Tea Lanisnik
TL
D015089:20-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D015096:3-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D000074425:Aldo-Keto Reductase Family 1 Member C3; D001665:Binding Sites; D003198:Computer Simulation; D003374:Coumarins / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D045166:Estradiol Congeners / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000494:pharmacology; D044950:Flavanones / Q000494:pharmacology; D047309:Flavones / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000378:metabolism; D007529:Isoflavones / Q000494:pharmacology; D008954:Models, Biological; D008958:Models, Molecular; D010616:Phenanthrenes / Q000037:antagonists & inhibitors; D048789:Phytoestrogens / Q000494:pharmacology*; D011374:Progesterone / Q000378:metabolism*; D011375:Progesterone Reductase / Q000378:metabolism; D011485:Protein Binding; D011994:Recombinant Proteins / Q000302:isolation & purification; D013267:Stilbenes / Q000494:pharmacology; D015025:Zearalenone / Q000494:pharmacology
D003374:Coumarins; D004791:Enzyme Inhibitors; D045166:Estradiol Congeners; D020847:Estrogen Receptor Modulators; D044950:Flavanones; D047309:Flavones; D007529:Isoflavones; D010616:Phenanthrenes; D048789:Phytoestrogens; D011994:Recombinant Proteins; D013267:Stilbenes; C005399:9,10-phenanthrenequinone; D011374:Progesterone; D015025:Zearalenone; C030123:coumarin; D015096:3-Hydroxysteroid Dehydrogenases; D015089:20-Hydroxysteroid Dehydrogenases; C115140:3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase; D006911:Hydroxyprostaglandin Dehydrogenases; D011375:Progesterone Reductase; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3; C005273:naringenin; C505898:coumestan; C028610:flavanone