Characterization of triptolide hydroxylation by cytochrome P450 in human and rat liver microsomes

被引：92

作者：

Li, W. ^{[1
,5
]}

Liu, Y. ^{[1
]}

He, Y. -Q. ^{[2
]}

Zhang, J. -W. ^{[1
]}

Gao, Y. ^{[3
]}

Ge, G. -B. ^{[1
,5
]}

Liu, H. -X. ^{[1
,5
]}

Huo, H. ^{[1
]}

Liu, H. -T. ^{[1
,5
]}

Wang, L. -M. ^{[3
]}

Sun, J. ^{[3
]}

Wang, Q. ^{[4
]}

Yang, L. ^{[1
]}

机构：

[1] Chinese Acad Sci, Dalian Inst Chem Phys, Lab Pharmaceut Resource Discovery, Dalian 116023, Peoples R China

[2] Shanghai Univ Tradit Chinese Med, Shanghai, Peoples R China

[3] Dalian Med Univ, Affiliated Hosp 2, Dalian, Peoples R China

[4] Dalian Univ Technol, Dalian, Peoples R China

[5] Chinese Acad Sci, Grad Univ, Beijing, Peoples R China

来源：

XENOBIOTICA | 2008年 / 38卷 / 12期

基金：

中国国家自然科学基金;

关键词：

Triptolide; cytochrome P450; mono-hydroxylated metabolite;

D O I：

10.1080/00498250802503359

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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.

引用

页码：1551 / 1565

页数：15

共 27 条

[1] Baranczewski P, 2006, PHARMACOL REP, V58, P453
[2] Tliptolide induces caspase-dependent cell death mediated via the mitochondfial pathway in leukemic cells
Carter, Bing Z.
Mak, Duncan H.
Schober, Wendy D.
McQueen, Teresa
Harris, David
Estrov, Zeev
Evans, Randall L.
Andreeff, Michael
[J]. BLOOD, 2006, 108 (02) : 630 - 637
[3] Triptolide, a novel immunosuppressive and anti-inflammatory agent purified from a Chinese herb Tripterygium Wilfordii Hook F
Chen, BJ
[J]. LEUKEMIA & LYMPHOMA, 2001, 42 (03) : 253 - 265
[4] AUTOCATALYTIC ALKYLATION OF THE CYTOCHROME-P-450 PROSTHETIC HEME GROUP BY 1-AMINOBENZOTRIAZOLE - ISOLATION OF AN NN-BRIDGED BENZENE-PROTOPORPHYRIN IX ADDUCT
DEMONTELLANO, PRO
MATHEWS, JM
[J]. BIOCHEMICAL JOURNAL, 1981, 195 (03) : 761 - 764
[5] Fidler JM, 2003, MOL CANCER THER, V2, P855
[6] Immunosuppressive activity of the Chinese medicinal plant Tripterygium wilfordii.: III.: Suppression of graft-versus-host disease in murine allogeneic bone marrow transplantation by the PG27 extract
Fidler, JM
Ku, GY
Piazza, D
Xu, RS
Jin, RL
Chen, ZQ
[J]. TRANSPLANTATION, 2002, 74 (04) : 445 - 457
[7] FIDLER JM, 2003, Patent No. 6620843
[8] GU WZ, 1995, INT J IMMUNOPHARMACO, V17, P351
[9] Cytochrome P450s and other enzymes in drug metabolism and toxicity
Guengerich, FP
[J]. AAPS JOURNAL, 2006, 8 (01) : E101 - E111
[10] HOUSTON JB, 1994, BIOCHEM PHARMACOL, V47, P1469

← 1 2 3 →