p450 - publications

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1. Xenobiotica. 2012 Apr 25. [Epub ahead of print]

Potent inhibition of CYP1A2 by Frutinone A, an active ingredient of the broad
spectrum antimicrobial herbal extract from P. fruticosa.

Thelingwani RS, Dhansay K, Smith P, Chibale K, Masimirembwa CM.

Department of DMPK/PD-BAC, African Institute of Biomedical Science & Technology
(AIBST) , Harare , Zimbabwe.

1. Frutinone is an active ingredient extracted from the lipophilic fraction of
the 1.Frutinone is an active ingredient extracted from the lipophilic fraction of
the Polygala Fruticosa demonstrating various antibacterial and fungal properties.
The aim of this study was to characterize its metabolism in an effort to
understand metabolism based drug-herb interactions. 2. In vitro metabolic
clearance and metabolite identification studies were done using cryopreserved
hepatocytes. Reaction phenotyping and inhibition studies were done using human
liver microsomes and recombinant cytochrome P450s (CYPs). Frutinone A-CYP1A2
interactions were rationalized using docking simulations. 3. Hepatic clearance
was predicted to be low (7.17 mL/min/kg), with reaction phenotyping studies
indicating no clearance by the enzymes tested. Frutinone was identified as a
potent inhibitor of CYP1A2 with moderate effects on CYP2C19, 2C9, 2D6 and 3A4.
CYP1A2 inhibition was reversible and characterised by an IC(50) of 0.56µM.
Inhibition was differential showing mixed (K(i) = 0.48 µM) and competitive (K(i)
= 0.31 µM) inhibition with 3-cyano-7-ethoxycoumarin and ethoxyresorufin,
respectively. Two binding sites, one for inhibitors and the other for substrates
were identified in silico. 4. The potent CYP1A2 inhibition by Frutinone A could
be predictive of the potential drug-herb interaction risk in the use of herbal
extracts from P. fruticosa. The data suggest future pharmacological research on
this chromocoumarin should take metabolic properties into account.

PMID: 22533317 [PubMed - as supplied by publisher]