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 (IC(50)=1.73 μM) and
CYP2C9 (IC(50)=8.61 μM), and weak inhibition on
CYP2D6 (IC(50)=30.20 μM) and
CYP3A4 (IC(50)=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.