Characterization of triptolide hydroxylation by cytochrome P450 in human and rat liver microsomes.
Triptolide, the primary active component of a traditional Chinese medicine Tripterygium wilfordii Hook F, has a wide range of pharmacological activities. In the present study, the metabolism of triptolide by cytochrome P450s was investigated in human and rat liver microsomes. Triptolide was converted to four metabolites (M-1, M-2, M-3, and M-4) in rat liver microsomes and three (M-2, M-3, and M-4) in human liver microsomes. All the products were identified as mono-hydroxylated triptolides by liquid chromatography-mass spectrometry (LC-MS). The studies with chemical selective inhibitors, complementary DNA-expressed human cytochrome P450s, correlation analysis, and enzyme kinetics were also conducted. The results demonstrate that CYP3A4 and CYP2C19 could be involved in the metabolism of triptolide in human liver, and that CYP3A4 was the primary isoform responsible for its hydroxylation.
Li
W
W
Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
Liu
Y
Y
He
Y-Q
YQ
Zhang
J-W
JW
Gao
Y
Y
Ge
G-B
GB
Liu
H-X
HX
Huo
H
H
Liu
H-T
HT
Wang
L-M
LM
Sun
J
J
Wang
Q
Q
Yang
L
L
D000818:Animals; D002853:Chromatography, Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D018076:DNA, Complementary / Q000235:genetics / Q000378:metabolism; D004224:Diterpenes / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004852:Epoxy Compounds / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D007700:Kinetics; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000201:enzymology* / Q000378:metabolism; D010616:Phenanthrenes / Q000378:metabolism*; D051381:Rats
D065607:Cytochrome P-450 Enzyme Inhibitors; D018076:DNA, Complementary; D004224:Diterpenes; D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D010616:Phenanthrenes; C001899:triptolide; D003577:Cytochrome P-450 Enzyme System