Enzyme kinetic and molecular docking studies for the inhibitions of miltirone on major human cytochrome P450 isozymes

Xuelin Zhou; Yan Wang; Tao Hu; Penelope M Y Or; John Wong; Yiu Wa Kwan; David C C Wan; Pui Man Hoi; Paul B S Lai; John H K Yeung

doi:10.1016/j.phymed.2012.09.021

Enzyme kinetic and molecular docking studies for the inhibitions of miltirone on major human cytochrome P450 isozymes

Xuelin Zhou, Yan Wang, Tao Hu, Penelope M Y Or, John Wong, Yiu Wa Kwan, David C C Wan, Pui Man Hoi, Paul B S Lai, John H K Yeung

Center for Drug Design

Research output: Contribution to journal › Article › peer-review

46 Scopus citations

Abstract

Previous studies have shown that major tanshinones isolated from Danshen (Salvia miltiorrhiza) inhibited human and rat CYP450 enzymes-mediated metabolism of model probe substrates, with potential in causing herb-drug interactions. Miltirone, another abietane type-diterpene quinone isolated from Danshen, has been reported for its anti-oxidative, anxiolytic and anti-cancer effects. The aim of this study was to study the effect of miltirone on the metabolism of model probe substrates of CYP1A2, 2C9, 2D6 and 3A4 in pooled human liver microsomes. Miltirone showed moderate inhibition on CYP1A2 (IC₅₀ = 1.73 μM) and CYP2C9 (IC₅₀ = 8.61 μM), and weak inhibition on CYP2D6 (IC₅₀ = 30.20 μM) and CYP3A4 (IC₅₀ = 33.88 μM). Enzyme kinetic studies showed that miltirone competitively inhibited CYP2C9 (K_i = 1.48 μM), and displayed mixed type inhibitions on CYP1A2, CYP2D6 and CYP3A4 with K_i values of 3.17 μM, 24.25 μM and 35.09 μM, respectively. Molecular docking study further confirmed the ligand-binding conformations of miltirone in the active sites of these human CYP450 isoforms, and provided some information on structure-activity relationships for the CYPs inhibition by tanshinones. Taken together, CYPs inhibitions of miltirone were weaker than dihydrotanshinone, but stronger than cryptotanshinone, tanshinone I and tanshinone IIA.

Original language	English (US)
Pages (from-to)	367-374
Number of pages	8
Journal	Phytomedicine
Volume	20
Issue number	3-4
DOIs	https://doi.org/10.1016/j.phymed.2012.09.021
State	Published - Feb 15 2013

Keywords

Cytochrome P450
Miltirone
Molecular docking
Probe substrates
Salvia miltiorrhiza

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title = "Enzyme kinetic and molecular docking studies for the inhibitions of miltirone on major human cytochrome P450 isozymes",

abstract = "Previous studies have shown that major tanshinones isolated from Danshen (Salvia miltiorrhiza) inhibited human and rat CYP450 enzymes-mediated metabolism of model probe substrates, with potential in causing herb-drug interactions. Miltirone, another abietane type-diterpene quinone isolated from Danshen, has been reported for its anti-oxidative, anxiolytic and anti-cancer effects. The aim of this study was to study the effect of miltirone on the metabolism of model probe substrates of CYP1A2, 2C9, 2D6 and 3A4 in pooled human liver microsomes. Miltirone showed moderate inhibition on CYP1A2 (IC50 = 1.73 μM) and CYP2C9 (IC50 = 8.61 μM), and weak inhibition on CYP2D6 (IC50 = 30.20 μM) and CYP3A4 (IC50 = 33.88 μM). Enzyme kinetic studies showed that miltirone competitively inhibited CYP2C9 (Ki = 1.48 μM), and displayed mixed type inhibitions on CYP1A2, CYP2D6 and CYP3A4 with Ki values of 3.17 μM, 24.25 μM and 35.09 μM, respectively. Molecular docking study further confirmed the ligand-binding conformations of miltirone in the active sites of these human CYP450 isoforms, and provided some information on structure-activity relationships for the CYPs inhibition by tanshinones. Taken together, CYPs inhibitions of miltirone were weaker than dihydrotanshinone, but stronger than cryptotanshinone, tanshinone I and tanshinone IIA.",

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author = "Xuelin Zhou and Yan Wang and Tao Hu and Or, {Penelope M Y} and John Wong and Kwan, {Yiu Wa} and Wan, {David C C} and Hoi, {Pui Man} and Lai, {Paul B S} and Yeung, {John H K}",

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AU - Zhou, Xuelin

AU - Wang, Yan

AU - Hu, Tao

AU - Or, Penelope M Y

AU - Wong, John

AU - Kwan, Yiu Wa

AU - Wan, David C C

AU - Hoi, Pui Man

AU - Lai, Paul B S

AU - Yeung, John H K

PY - 2013/2/15

Y1 - 2013/2/15

N2 - Previous studies have shown that major tanshinones isolated from Danshen (Salvia miltiorrhiza) inhibited human and rat CYP450 enzymes-mediated metabolism of model probe substrates, with potential in causing herb-drug interactions. Miltirone, another abietane type-diterpene quinone isolated from Danshen, has been reported for its anti-oxidative, anxiolytic and anti-cancer effects. The aim of this study was to study the effect of miltirone on the metabolism of model probe substrates of CYP1A2, 2C9, 2D6 and 3A4 in pooled human liver microsomes. Miltirone showed moderate inhibition on CYP1A2 (IC50 = 1.73 μM) and CYP2C9 (IC50 = 8.61 μM), and weak inhibition on CYP2D6 (IC50 = 30.20 μM) and CYP3A4 (IC50 = 33.88 μM). Enzyme kinetic studies showed that miltirone competitively inhibited CYP2C9 (Ki = 1.48 μM), and displayed mixed type inhibitions on CYP1A2, CYP2D6 and CYP3A4 with Ki values of 3.17 μM, 24.25 μM and 35.09 μM, respectively. Molecular docking study further confirmed the ligand-binding conformations of miltirone in the active sites of these human CYP450 isoforms, and provided some information on structure-activity relationships for the CYPs inhibition by tanshinones. Taken together, CYPs inhibitions of miltirone were weaker than dihydrotanshinone, but stronger than cryptotanshinone, tanshinone I and tanshinone IIA.

AB - Previous studies have shown that major tanshinones isolated from Danshen (Salvia miltiorrhiza) inhibited human and rat CYP450 enzymes-mediated metabolism of model probe substrates, with potential in causing herb-drug interactions. Miltirone, another abietane type-diterpene quinone isolated from Danshen, has been reported for its anti-oxidative, anxiolytic and anti-cancer effects. The aim of this study was to study the effect of miltirone on the metabolism of model probe substrates of CYP1A2, 2C9, 2D6 and 3A4 in pooled human liver microsomes. Miltirone showed moderate inhibition on CYP1A2 (IC50 = 1.73 μM) and CYP2C9 (IC50 = 8.61 μM), and weak inhibition on CYP2D6 (IC50 = 30.20 μM) and CYP3A4 (IC50 = 33.88 μM). Enzyme kinetic studies showed that miltirone competitively inhibited CYP2C9 (Ki = 1.48 μM), and displayed mixed type inhibitions on CYP1A2, CYP2D6 and CYP3A4 with Ki values of 3.17 μM, 24.25 μM and 35.09 μM, respectively. Molecular docking study further confirmed the ligand-binding conformations of miltirone in the active sites of these human CYP450 isoforms, and provided some information on structure-activity relationships for the CYPs inhibition by tanshinones. Taken together, CYPs inhibitions of miltirone were weaker than dihydrotanshinone, but stronger than cryptotanshinone, tanshinone I and tanshinone IIA.

KW - Cytochrome P450

KW - Miltirone

KW - Molecular docking

KW - Probe substrates

KW - Salvia miltiorrhiza

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Enzyme kinetic and molecular docking studies for the inhibitions of miltirone on major human cytochrome P450 isozymes

Abstract

Keywords

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