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 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.
Lee
Sang Kyu
SK
Doping Control Center, Korea Institute of Science and Technology, P.O. Box 131, Chungryang, Seoul 136-791, Korea.
Jun
In Hye
IH
Yoo
Hye Hyun
HH
Kim
Ju Hyun
JH
Seo
Young Min
YM
Kang
Mi Jeong
MJ
Lee
Seung Ho
SH
Jeong
Tae Cheon
TC
Kim
Dong Hyun
DH
D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D003580:Cytochromes / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004365:Drugs, Chinese Herbal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007306:Insecticides / Q000032:analysis* / Q000493:pharmacokinetics; D007527:Isoenzymes / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000737:chemistry* / Q000378:metabolism; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000032:analysis / Q000493:pharmacokinetics; D011522:Protons; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism; D053719:Tandem Mass Spectrometry
D003580:Cytochromes; D018076:DNA, Complementary; D004365:Drugs, Chinese Herbal; D004791:Enzyme Inhibitors; D007306:Insecticides; D007527:Isoenzymes; D011522:Protons; D011994:Recombinant Proteins; C014451:deoxypodophyllotoxin; D011034:Podophyllotoxin