TM208在大鼠肝微粒体中代谢产物与细胞色素P450亚型代谢酶鉴别研究

TM208在大鼠肝微粒体中代谢产物与细胞色素P450亚型代谢酶鉴别研究

孔德涛, 凌笑梅^*, 韩方斌, 龚京莉, 葛泽梅, 李润涛, 崔景荣^**

1.北京大学药学院化学生物学系, 北京 100083;
2. 北京大学天然药物及仿生药物国家重点实验室, 北京 100083

收稿日期:2007-11-09 修回日期:2008-01-10 出版日期:2008-03-15 发布日期:2008-03-15
通讯作者: 凌笑梅*, 崔景荣**

Identification of the metabolite and cytochrome P450 isoforms involved in rat liver microsomal metabolism of TM208

De-Tao Kong, Xiao-Mei Ling^*, Fang-Bin Han, Jing-Li Gong, Ze-Mei Ge, Run-Tao Li, Jing-Rong Cui^**

1. Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100083, China;
2. The State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100083, China

Received:2007-11-09 Revised:2008-01-10 Online:2008-03-15 Published:2008-03-15
Contact: Xiao-Mei Ling*, Jing-Rong Cui**

摘要/Abstract

摘要：

在大鼠肝微粒体的体外代谢中研究作用于TM208的细胞色素P450亚型代谢酶。以不含细胞色素P450化学抑制剂的样品为对照, 研究不同细胞色素P450亚型选择性化学抑制剂对TM208代谢转化率的影响。CYP2D和CYP2B的选择性抑制剂对TM208的代谢表现出浓度依赖性较强抑制作用, CYP1A的选择性抑制剂对TM208的代谢表现出一定抑制作用。CYP3A的选择性抑制剂对TM208的代谢没有表现出明显的抑制作用。TM208在大鼠肝微粒体体外代谢中主要通过CYP2D和CYP2B两种细胞色素P450亚型代谢酶参与代谢。

关键词: TM208, TM208, TM208, 大鼠肝微粒体, 大鼠肝微粒体, 大鼠肝微粒体, 代谢, 代谢, 代谢, 细胞色素P450亚型代谢酶, 细胞色素P450亚型代谢酶, 细胞色素P450亚型代谢酶

Abstract:

To identify the metabolite and CYP450 isoforms involved in rat liver microsomal metabolism of TM208. The present study investigated the metabolism of TM208 and the effects of selective CYP450 inhibitors on the metabolism of TM208 in rat liver microsomes. Various specific inhibitors of CYP were used to identify the isoforms of CYP involved in the metabolism of TM208. The inhibitor of CYP2D and that of CYP2B had strong inhibitory effects on TM208 metabolism in a concentration-dependant manner, the inhibitor of CYP1A had a modest inhibitory effect, and the inhibitor of CYP3A seemed not to have an obvious inhibitory effect on TM208 metabolism. TM208 might mainly be metabolized by CYP2D and CYP2B in rat liver microsomes.

Key words: TM208, TM208, Rat liver microsomes, Rat liver microsomes, Metabolism, Metabolism, Cytochrome P450 isoform, Cytochrome P450 isoform

中图分类号:

R917

Supporting: Foundation item: National Basic Research Program of China (863 Program, Grant No. 2004AA2Z3783) and National Natural Science Foundation of China (Grant No. 20672009).
^*Corresponding authors. ^*Tel.: 86-10-82801590; fax: 86-10-82802414;
^**Tel./fax: 86-10-82802467

孔德涛, 凌笑梅^*, 韩方斌, 龚京莉, 葛泽梅, 李润涛, 崔景荣^**. TM208在大鼠肝微粒体中代谢产物与细胞色素P450亚型代谢酶鉴别研究[J]. .

De-Tao Kong, Xiao-Mei Ling^*, Fang-Bin Han, Jing-Li Gong, Ze-Mei Ge, Run-Tao Li, Jing-Rong Cui^**. Identification of the metabolite and cytochrome P450 isoforms involved in rat liver microsomal metabolism of TM208[J]. .

参考文献

[1] Len, C.; Boulognemerlot, A.S.; Posted, D. J. Agric. Food Chem. 1996, 44, 2856–2858.
[2] Nieuwenhuizen, P.J. Appl. Catal. A. Gen. 2001, 207, 55–68.
[3] Schilli, C.; Lanzendorfer, M.G.; Muller, A.H.E. Macro-molecules. 2002, 35, 6819–6827.
[4] Fujii, S.; Yoshimura, T. Coord. Chem. Rev. 2000, 198, 89–99.
[5] Bessho, R.; Matsubara, K.; Kubota, M.; Kuwakado, K.; Hirota, H.; Wakazono, Y.; Ying, W.L.; Okuda, A.; Kawai, M.; Nishikomori, R.; Heike, T.; Bessho, R.; Matsubara, K.; Kubota, M. Biochem. Pharmacol. 1994, 48, 1883–1889.
[6] Tsai, J.C.; Jain M.; Hsieh, C.M.; Lee, W.S.; Yoshizumi, M.; Patterson, C.; Perrella, M.A.; Cooke, C.; Wang, H.; Haber, E.; Schlegel, R.; Lee, M.E. J. Biol. Chem. 1996, 271, 3667–3670.
[7] Guo, B.G.; Ge, Z.M.; Cheng, T.M.; Li, R.T. Acta. Pharmacol. Sin. 2001, 36, 185–190.
[8] Ge, Z.M.; Li, R.T.; Cheng, T.M.; Cui, J.R. Arch. Der-Pharmazie. Med. Chem. 2001, 334, 173–176.
[9] Guo, W.; Ran, F.X.; Wang, R.O.; Cui, J.R.; Li, R.T.; Cheng, T.M.; Ge, Z.M. Chin. J. Clin. Pharm. Ther. 2004, 9, 59–62.
[10] Jiang, X.M.; Kong, D.T.; Han, F.B.; Ling, X.M.; Liu, X.Y.; Li, R.T.; Cui, J.R. Rapid Commun. Mass Spectrum. 2007, 21, 1599–1595.
[11] Jiang, X.M.; Ling, X.M.; Han F.B.; Li, R.T.; Cui, J.R. J. Pharm. Biomed. Anal. 2007, 45, 1127–1132.
[12] Jiang, X.M.; Ling, X.M.; Han, F.B.; Li, R.T.; Cui, J.R. J. Sep. Sci. 2007, 30, 2080–2085.
[13] Rettie, A.E.; Eddy, A.C.; Heimark, L.D.; Gibaldi, M.; Trager, W.F. Drug Metab. Dispos. 1989, 17, 265–270.
[14] Huang, Z.Q.; Roy, P.; Waxman, D.J. Biochem. Pharmacol. 2000, 59, 561–570.
[15] Lakshmi, V.M.; Zenser, T.V.; Davis, B.B. Drug Metab. Dispos. 1997, 25, 481–488.
[16] Hasegawa, T.; Hara, K.; Kenmochi, T.; Hata S. Drug Metab. Dispos. 1994, 22, 916–921.
[17] Kobayashi, S.; Murray, S.; Watson, D.; Sesardic, D.; Davies, D.S.; Boobis, A.R. Biochem. Pharmacol. 1989, 38, 2795–2799.
[18] Soledade, M.; Pedras, C.; Taylor, J.L. J. Nat. Prod. 1993, 56, 731–738.
[19] Soledade, M.; Pedras, C.; Taylor, J.L. J. Org. Chem. 1991, 56, 2619–2621.
[20] Segall, Y.; Casidav, J.E. J. Agric. Food Chem. 1983, 31, 242–246.
[21] Anzenbacher, P.; Anzebacherova, E. Cell Mol. Life Sci. 2001, 58, 737–747.
[22] Rendic, S.; DiCarlo, F.J. Drug Metab. Rev. 1997, 29, 413–458.
[23] Scripture, C.D.; Figg, W.D. Nat. Rev. Cancer 2006, 6, 546-558.
[24] Anzenbacher, P.; Anzenbacherova, E. Cell Mol. Life Sci. 2001, 58, 737–747.
[25] Ingelman-Sundberg, M. Trends Pharmacol. Sci. 2004, 25, 193–200.
[26] Gonzalez, F.J.; Skoda, R.C.; Kimura, S. Nature. 1988, 331, 442–446.
[27] Bertilsson, L. Clin. Pharmacokinet. 1995, 29, 192–209.
[28] Smith, D.A.; Abel, S.M.; Hyland, R.; Jones, B.C. Xenobiotica. 1998, 28, 1095–1128.
[29] Bertilsson, L. Clin. Pharmacokinet. 1995, 29, 192–209.
[30] Horai, Y.; Nakano, M.; Ishizaki, T.; Ishikama, K.; Zhou H.; Zhou, B.; Liao, C.; Zhang, L. Chin. J. Clin. Pharmacol. Ther. 1989, 46, 98–207.
[31] Matsunaga, E.; Zanger, U.M.; Hardwick, J.P. Biochemistry. 1989, 28, 7349–7355.