Cytochrome P450 reaction phenotyping and inhibition and induction studies of pinostrobin in human liver microsomes and hepatocytes

Abstract

Pinostrobin (PI, 5-hydroxy-7-methoxyflavanone) is a natural flavonoid known for its rich pharmacological activities. The objective of this study was to identify the human liver cytochrome P450 (CYP450) isoenzymes involved in the metabolism of PI. A single hydoxylated metabolite was obtained from PI after an incubation with pooled human liver microsomes (HLMs). The relative contributions of different CYP450s were evaluated using CYP450-selective inhibitors in HLMs and recombinant human CYP450 enzymes, and the results revealed the major involvement of CYP1A2, CYP2C9 and CYP2E1 in PI metabolism. We also evaluated the ability of PI to inhibit and induce human cytochrome P450 enzymes in vitro. High-performance liquid chromatography and liquid chromatography-tandem mass spectrometry analytical techniques were used to estimate the enzymatic activities of seven drug-metabolizing CYP450 isozymes in vitro. In HLMs, PI did not inhibit CYP 1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4 (IC > 100 μm). In the induction studies, PI had minimal effects on CYP1A2, CYP2B6and CYP3A4 activity. Based on these results, PI would not be expected to cause clinically significant CYP450 inhibition or induction.

UHPLC-Q-TOF-MS/MS Method Based on Four-Step Strategy for Metabolism Study of Fisetin in Vitro and in Vivo

“…Cytochrome P450 (CYP450) plays an important role in the phase I metabolism of a wide variety of compounds (endogenous and exogenous) . Moreover, CYP1A2, CYP2C9, and CYP2E1 were the main metabolic subtype of CYP450 for flavone . And transmethylase, sulfotransferase (ST), and UDP-glucuronosyltransferases (UGTs) were the main metabolic enzymes of phase II.…”

“…33 Moreover, CYP1A2, CYP2C9, and CYP2E1 were the main metabolic subtype of CYP450 for flavone. 34 And transmethylase, 35 sulfotransferase (ST), 36 and UDP-glucuronosyltransferases (UGTs) 37 were the main metabolic enzymes of phase II. Furthermore, UGT1A1, UGT1A3, UGT1A9, UGT1A10, and UGT2B7 mainly participated in glucuronide conjugation reaction of flavone.…”

Pinostrobin Inhibits Proprotein Convertase Subtilisin/Kexin-type 9 (PCSK9) Gene Expression through the Modulation of FoxO3a Protein in HepG2 Cells

“…Hepatic CYP1A2, CYP2C9, and CYP2E1 were the primary enzymes responsible for the formation of the hydroxylated metabolite of pinostrobin. 39 In this study, we investigated the in vitro effects of pinostrobin on hepatic cell line. We demonstrated inhibition of PCSK9 gene expression by pinostrobin at concentrations 20−40 μM, which are used in vitro cell culture system, though it is higher than what can be achieved in vivo.…”

“…In in vitro studies, it has been reported that pinostrobin was converted into hydroxylated metabolite of pinostrobin by human liver microsomes. Hepatic CYP1A2, CYP2C9, and CYP2E1 were the primary enzymes responsible for the formation of the hydroxylated metabolite of pinostrobin . In this study, we investigated the in vitro effects of pinostrobin on hepatic cell line.…”

Pharmacokinetic study on the effect of ligustrazine–tangeretin co‐administration on the pharmacokinetics of ligustrazine and its potential mechanism in rats

“…Tangeretin was previously demonstrated to induce the activity of CYP3A4, a major isoenzyme of CYP450 and responsible for the metabolism of ligustrazine. 17,18 Therefore, it was speculated that the coadministration of tangeretin with ligustrazine might induce changes in the pharmacokinetics of ligustrazine via inducing CYP3A4, which was investigated in this study.…”