coumestan and flavanone

The fruit of Psoralea corylifolia (Psoraleae Fructus) is a traditional Chinese medicine (TCM), which has been used to prevent and treat vitiligo, psoriasis, and osteoporosis in China for thousands of years. Phytochemical investigation on Psoraleae Fructus, as well as some metabolism research focused on pharmacokinetics of several single compounds from this plant, has been reported. However, the effective material of Psoraleae Fructus is still unknown. In the present study, the metabolic fate of multiple components of Psoraleae Fructus in rats was investigated by ultra performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC/Q-TOF-MS). Based on a three-step strategy, a total of 142 Psoraleae Fructus-related xenobiotics were identified or tentatively characterized in rat biofluids after oral administration of six representative single compounds and Psoraleae Fructus extract. All six different types of constituents of Psoraleae Fructus, including furocoumarin, coumestan, isoflavone, flavanone, chalcone and monoterpene phenol, could be absorbed into the circulation system. In addition, compared with the metabolism of six representative single compounds, different metabolic fate was observed after oral administration of Psoraleae Fructus extract, which indicated that the drug-drug interactions occurred when fed by multi-component herbal extract, and the investigations only focused on several main components were not sufficient to represent and reflect the overall efficacy of plants. The present study will be conducive to further pharmacological mechanism research on Psoraleae Fructus.

Topics: Administration, Oral; Animals; Chalcone; Chromatography, High Pressure Liquid; Coumarins; Drug Interactions; Drugs, Chinese Herbal; Flavanones; Fruit; Furocoumarins; Isoflavones; Male; Medicine, Chinese Traditional; Phenols; Plant Extracts; Psoralea; Rats; Rats, Sprague-Dawley; Tandem Mass Spectrometry

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.

Topics: 20-Hydroxysteroid Dehydrogenases; 3-Hydroxysteroid Dehydrogenases; Aldo-Keto Reductase Family 1 Member C3; Binding Sites; Computer Simulation; Coumarins; Enzyme Inhibitors; Estradiol Congeners; Estrogen Receptor Modulators; Flavanones; Flavones; Humans; Hydroxyprostaglandin Dehydrogenases; Isoflavones; Models, Biological; Models, Molecular; Phenanthrenes; Phytoestrogens; Progesterone; Progesterone Reductase; Protein Binding; Recombinant Proteins; Stilbenes; Zearalenone