Screening of flavonoid aglycons’ metabolism mediated by the human liver cytochromes P450

Abstract

Biological effects of flavonoids have been extensively studied in the last 80 years. As flavonoids represent a rather large group of compounds, data on metabolic biotransformations of these compounds is relatively limited to those well studied. The objective of this study was to screen the metabolism of 30 selected flavonoid aglycons mediated by the most relevant metabolic enzymes, human liver cytochromes P450. For this purpose, in vitro experiments with human liver microsomes and recombinant enzymes were conducted. To evaluate flavonoid’s metabolism and structure of the products, high-performance liquid chromatography coupled with high-resolution mass spectrometry was used. Out of 30 flavonoids, 15 were susceptible to oxidative metabolism mediated by cytochromes P450. Dominant reactions were aromatic hydroxylation and O-demethylation, or a combination of these reactions. The dominant enzyme responsible for the observed metabolic reactions is CYP1A2, whereas other human liver cytochromes P450, namely, CYP2C19, CYP2D6, CYP2E1 and CYP3A4, contribute to flavonoid metabolism to a lesser degree. These results, to some extent, contribute to the understanding of the metabolism of constituents found in antioxidant dietary supplements and their possible interactions with other xenobiotics, i.e., medicinal products.

Characterization of O-demethylations and Aromatic Hydroxylations Mediated by Cytochromes P450 in the Metabolism of Flavonoid Aglycons

“…These were flavonoids that showed metabolite formation in the amount of at least 10 % (m/m) in comparison with the amount of substrate in the human liver microsomes screening experiments. [34] An example of methodology used to determine kinetic parameters is provided in Figure 1.…”

“…[18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] In the previous study, screening of metabolic reactions mediated by cytochrome P450 was conducted on thirty flavonoid aglycons, most commonly found in medicinal plants and propolis. [34] Flavonoid aglycons are subject to O-demethylation and aromatic hydroxylation reactions, and their metabolism includes cytochrome P450, predominantly CYP1A2. [34] The aim of this study was to determine the enzymatic kinetics of Odemethylation and aromatic hydroxylation of flavonoid aglycons that have been shown to be susceptible to the metabolism mediated by human liver cytochromes P450 in the previously reported screening analysis.…”

“…[34] Flavonoid aglycons are subject to O-demethylation and aromatic hydroxylation reactions, and their metabolism includes cytochrome P450, predominantly CYP1A2. [34] The aim of this study was to determine the enzymatic kinetics of Odemethylation and aromatic hydroxylation of flavonoid aglycons that have been shown to be susceptible to the metabolism mediated by human liver cytochromes P450 in the previously reported screening analysis. [34] The study was performed on ten flavonoids, namely 3,7-dihydroxyflavone, 7-hydroxyflavone, acacetin, apigenin, flavone, galangin, kaempferol, naringenin, sakuranetin, and tangeretin using the recombinant cytochrome P450 enzymes and human liver microsomes.…”

“…[34] The aim of this study was to determine the enzymatic kinetics of Odemethylation and aromatic hydroxylation of flavonoid aglycons that have been shown to be susceptible to the metabolism mediated by human liver cytochromes P450 in the previously reported screening analysis. [34] The study was performed on ten flavonoids, namely 3,7-dihydroxyflavone, 7-hydroxyflavone, acacetin, apigenin, flavone, galangin, kaempferol, naringenin, sakuranetin, and tangeretin using the recombinant cytochrome P450 enzymes and human liver microsomes. Reactions were monitored using the liquid chromatography coupled with mass spectrometer and UV detector.…”

Regioselective Hydroxylation of Phloretin, a Bioactive Compound from Apples, by Human Cytochrome P450 Enzymes

“…Phlorizin is known to be a specific competitive inhibitor of SGLTs in intestines (SGLT-1) and kidneys (SGLT-2), and it seems to show beneficial effects on obesity and diabetes [8]. The major cytochrome P450 (P450 or CYP) enzyme involved in the metabolic reactions of flavonoids is CYP1A2, whereas other human liver P450s (such as CYP3A4, CYP2D6, CYP2E1, CYP2C19, and CYP2E1) contributed as minor roles to flavonoid metabolism when the metabolisms of 30 flavonoid aglycones were screened using human liver P450 enzymes [9]. The main oxidation reaction is hydroxylation at the carbon in the phenyl ring.…”