engleski

OXIDATIVE METABOLISM OF SAKURANETIN IN HUMANS

Sakuranetin is natural plant polyphenol that has shown antiviral, anti- inflammatory, antiprotozoal, antimicrobial, antidiabetic and anticancer properties. In human body it is primarily susceptible to oxidative reactions mediated by cytochrome P450 enzymes. The objective of this study was to determine types of oxidative reactions in the metabolism of sakuranetin mediated by aforementioned enzymes. Human liver microsomes (HLM) were used as source of enzymes. Metabolism was monitored by liquid chromatography coupled with mass spectrometry (electrospray ionization, time of flight detection) for metabolites determination and diode array detector for quantification. Specific cytochrome P450 enzymes involved in metabolism of sakuranetin were determined using specific inhibitors of each liver cytochrome P450. In HLM incubations, demethylation at position 7 of the A ring produces naringenin (mass loss of 14.016). Naringenin was further susceptible to aromatic hydroxylation at the position 3' of the B ring, producing eriodictyol (mass increase of 15.995). A third product of sakuranetin metabolism was formed by aromatic hydroxylation at the position 3' of the B ring, producing 5, 3', 4'-trihydroxy-7- methoxyflavonone. Kinetic parameters were determined for the combined reaction sakuranetin → naringenin → eriodictyol catalyzed by cytochromes P450 using the human liver microsomes as a source of enzyme. Rate constant was 3.1 ± 0.3 pM min–1 pM–1 and Km value was 152 ± 31 μM corresponding to the efficiency constant of (0.020 ± 0.005) × 106 M– 1 min–1. Based on the inhibitions with a specific cytochrome P450 enzyme, CYP2C9 and CYP2E1 were determined to be the most significant enzymes involved in metabolism of sakuranetin.

flavonoids, metabolism

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