Characterization of in vitro metabolites of deoxypodophyllotoxin in human and rat liver microsomes using liquid chromatography/tandem mass spectrometry

The in vitro metabolism of deoxypodophyllotoxin (DPT), a medicinal herbal product isolated from Anthriscus sylvestris (Apiaceae), was investigated in rats and human microsomes and human recombinant cDNA‐expressed CYPs. The incubation of DPT with pooled human microsomes in the presence of NADPH gener...

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Bibliographic Details
Published in:Rapid communications in mass spectrometry 2008-01, Vol.22 (1), p.52-58
Main Authors: Lee, Sang Kyu, Jun, In Hye, Yoo, Hye Hyun, Kim, Ju Hyun, Seo, Young Min, Kang, Mi Jeong, Lee, Seung Ho, Jeong, Tae Cheon, Kim, Dong Hyun
Format: Article
Language:English
Subjects:
Animals
Biotransformation
Chromatography, High Pressure Liquid
Cytochromes - analysis
Cytochromes - antagonists & inhibitors
Cytochromes - metabolism
DNA, Complementary - biosynthesis
DNA, Complementary - genetics
Enzyme Inhibitors - pharmacology
Humans
In Vitro Techniques
Insecticides - analysis
Insecticides - pharmacokinetics
Isoenzymes - analysis
Isoenzymes - antagonists & inhibitors
Isoenzymes - metabolism
Male
Microsomes, Liver - chemistry
Microsomes, Liver - metabolism
Podophyllotoxin - analogs & derivatives
Podophyllotoxin - analysis
Podophyllotoxin - pharmacokinetics
Protons
Rats
Rats, Sprague-Dawley
Recombinant Proteins - metabolism
Tandem Mass Spectrometry
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Summary:The in vitro metabolism of deoxypodophyllotoxin (DPT), a medicinal herbal product isolated from Anthriscus sylvestris (Apiaceae), was investigated in rats and human microsomes and human recombinant cDNA‐expressed CYPs. The incubation of DPT with pooled human microsomes in the presence of NADPH generated five metabolites while its incubation with dexamethasone (Dex)‐induced rat liver resulted in seven metabolites (M1–M7) with major metabolic reactions including mono‐hydroxylation, O‐demethylation and demethylenation. Reasonable structures of the seven metabolites of DPT could be proposed, based on the electrospray tandem mass spectra. Chemical inhibition by ketoconazole and metabolism studies with human recombinant cDNA‐expressed CYPs indicated that CYP 3A4 and 2C19 are the major CYP isozymes in the metabolism of DPT in human liver microsomes. Copyright © 2007 John Wiley & Sons, Ltd.
ISSN:0951-4198
1097-0231
DOI:10.1002/rcm.3325