Browse > Article
http://dx.doi.org/10.4062/biomolther.2008.16.3.190

Characterization of Deoxypodophyllotoxin Metabolism in Rat Liver Microsomes  

Lee, Sang-Kyu (College of Pharmacy, Yeungnam University)
Jun, In-Hye (College of Pharmacy, Yeungnam University)
Kang, Mi-Jeong (College of Pharmacy, Yeungnam University)
Jeon, Tae-Won (College of Pharmacy, Yeungnam University)
Kim, Ju-Hyun (College of Pharmacy, Yeungnam University)
Seo, Young-Min (College of Pharmacy, Yeungnam University)
Shin, Sil (College of Pharmacy, Yeungnam University)
Choi, Jae-Ho (College of Pharmacy, Yeungnam University)
Jeong, Hye-Gwang (College of Pharmacy, Chosun University)
Lee, Seung-Ho (College of Pharmacy, Yeungnam University)
Jeong, Tae-Cheon (College of Pharmacy, Yeungnam University)
Publication Information
Biomolecules & Therapeutics / v.16, no.3, 2008 , pp. 190-196 More about this Journal
Abstract
Deoxypodophyllotoxin (DPT) is a medicinal herb product isolated from Anthriscus sylvestris. DPT possesses beneficial activities in regulating immediate-type allergic reaction and anti-inflammatory activity through the dual inhibition of cyclooxygenase-2 and 5-lipoxygenase. In the present study, the metabolism of DPT was further characterized in rat liver microsomes isolated from male Sprague Dawley rats. The metabolism of DPT was NADPH-dependent. In addition, when liver microsomes were incubated with SKF-525A, a well-known CYP inhibitor, in the presence of $\beta$-NADPH, the metabolism of DPT was significantly inhibited. Using enriched rat liver microsomes, the anticipated isoforms of cytochrome P450s (CYPs) in the metabolism of DPT were partially characterized. Phenobarbital-induced microsomes increased in the formation of metabolite M1. The metabolite M3 was only produced in the enriched microsomes isolated from dexamethasone-treated rats. The results indicated that the metabolism of DPT would be CYP-dependent and that CYP2B and CYP3A might be important in the metabolism of DPT in rats.
Keywords
Deoxypodophyllotoxin; Metabolism; Cytochrome P450; in vitro; Electrospray ionization tandem mass spectrometry; Microsome;
Citations & Related Records

Times Cited By Web Of Science : 1  (Related Records In Web of Science)
Times Cited By SCOPUS : 1
연도 인용수 순위
1 Koulman, A., Kubbinga, M.E., Batterman, S., Woerdenbag, H.J., Pras, N., Woolley, J.G., and Quax, W.J. (2003c) A phytochemical study of lignans in whole plants and cell suspension cultures of Anthriscus sylvestris. Planta Med. 69, 733-738   DOI   ScienceOn
2 Bogucki, D.E. and Charlton, J.L. (1995) An asymmetric synthesis of (-)-deoxypodophyllotoxin. J. Org. Chem. 60, 588-593   DOI   ScienceOn
3 Chen, J.J., Chang, Y.L., Teng, C.M., and Chen, I.S. (2000) Antiplatelet aggregation alkaloids and lignans from Hernandia nymphaeifolia. Planta Med. 66, 251-256   DOI   ScienceOn
4 Gordaliza, M., Castro, M.A., Garcia-Gravalos, M.D., Ruiz, P., Miguel del Corral, J.M., and San Feliciano, A. (1994) Antineoplastic and antiviral activities of podophyllotoxin related lignans. Arch. Pharm. 327, 175-179   DOI   ScienceOn
5 Gross, G. (2001) Clinical diagnosis and management of anogenital warts and papillomavirus-associated lesions. Hautarzt. 52, 6-17   DOI
6 Ikeda, R., Nagao, T., Okabe, H., Nakano, Y., Matsunaga, H., Katano, M., and Mori, M. (1998) Antiproliferative constituents in Umbelliferae plants. IV. Constituents in the fruits of Anthriscus sylvestris Hoffm. Chem. Pharm. Bull. 46, 875-878   DOI   ScienceOn
7 Inamori, Y., Kato, Y., Kubo, M., Baba, K., Ishida, T., Nomoto, K., and Kozawa, M. (1985) The biological actions of deoxypodophyllotoxin (anthricin). I. Physiological activities and conformational analysis of deoxypodophyllotoxin. Chem. Pharm. Bull. 33, 704-709   DOI   ScienceOn
8 Jin, M., Moon, T.C., Quan, Z., Lee, E., Kim, Y.K., Yang, J.H., Suh, S.J., Jeong, T.C., Lee, S.H., Kim, C.H., Chang, H.W. (2008) The naturally occurring flavolignan, deoxypodophyllotoxin, inhibits lipopolysaccharide-induced iNOS expression through the NF-kB activation in RAW264.7 macrophage cells. Biol. Pharm. Bull. 31, 1312-1315   DOI   ScienceOn
9 Julsing, M.K., Vasilev, N.P., Schneidman-Duhovny, D., Muntendam, R., Woerdenbag, H.J., Quax, W.J., Wolfson, H.J., Ionkova, I., and Kayser, O. (2007) Metabolic stereoselectivity of cytochrome P450 3A4 towards deoxypodophyllotoxin: In silico predictions and experimental validation. Eur. J. Med. Chem. 19, 1-9
10 Kim, Y., Kim, S.B., You, Y.J., and Ahn, B.Z. (2002) Deoxypodophyllotoxin; the cytotoxic and antiangiogenic component from Pulsatilla koreana. Planta Med. 68, 271-274   DOI   ScienceOn
11 Lee, S.K., Jun, I.H., Yoo, H.H., Kim, J.H., Seo, Y.M., Kang, M.J., Lee, S.H., Jeong, T.C., and Kim, D.H. (2008) Characterization of in vitro metabolites of deoxypodophyllotoxin in human and rat liver microsomes using liquid chromatography/tandem mass spectrometry. Rapid Commun. Mass Spectrom. 22, 52-58   DOI   ScienceOn
12 Koulman, A., Beekman, A.C., Pras, N., and Quax, W.J. (2003a) The bioconversion process of deoxypodophyllotoxin with Linum flavum cell cultures. Planta Med. 69, 739-744   DOI   ScienceOn
13 Koulman, A., Batterman, S., van Putten, F. M. S., Bos, R., and Quax, W. J. (2003b) Lignan profiles of indoor-cultivated Anthriscus sylvestris. Planta Med. 69, 959-961   DOI   ScienceOn
14 Lee, S.H., Son, M.J., Ju, H.K., Lin, C.X., Moon, T.C., Choi, H.G., Son, J.K., and Chang, H.W. (2004) Dual inhibition of cyclooxygenase- 2 and 5-lipoxygenase by deoxypodophyllotoxin in mouse bone marrow-derived mast cells. Biol. Pharm. Bull. 27, 786-788   DOI   ScienceOn
15 Lim, Y.H., Lee, M.J., Shin, D.H., Chang, H.B., Hong, S.W., Moon, E.Y., Lee, D.K., Yoon, S.J., and Woo, W.S. (1999) Cytotoxic constituents from the roots of Anthriscus sylvestris. Arch. Pharm. Res. 22, 208-212   DOI   ScienceOn
16 Lowry, O.H., Rosenbrough, N.J., Farr, A.L., and Randall, R.J. (1951) Protein measurement with the folin phenol reagent. J. Biol. Chem. 193, 265-275
17 Masuda, T., Oyama, Y., Yonemori, S., Takeda, Y., Yamazaki, Y., Mizuguchi, S., Nakata, M., Tanaka, T., Chikahisa, L., Inaba, Y., and Okada, Y. (2002) Flow cytometric estimation on cytotoxic activity of leaf extracts from seashore plants in subtropical Japan: Isolation, quantification and cytotoxic action of (-) deoxypodophyllotoxin. Phytother. Res. 16, 353-358   DOI   ScienceOn
18 Sudo, K., Konno, K., Shigeta, S., and Yokota, T. (1998) Inhibitory effects of podophyllotoxin derivatives on herpes simplex virus replication. Antivir. Chem. Chemother. 9, 263-267   DOI
19 Molog, G.A., Empt, U., Kuhlmann, S., van Uden, W., Pras, N., Alfermann, A.W., and Petersen, M. (2001) Deoxypodophyllotoxin 6-hydroxylase, a cytochrome P450 monooxygenase from cell cultures of Linum flavum involved in the biosynthesis of cytotoxic lignans. Planta 214, 288-294   DOI
20 Myung, S.W., Kim, H.Y., Min, H.K., Kim, D.H., Kim, M., Cho, H.W., Lee, H.S., Kim, J.K., and Hong, C.I. (2002) The identification of in vitro metabolites of CKD-732 by liquid chromatography/ tandem mass spectrometry. Rapid Commun. Mass Spectrom. 16, 2048-2053   DOI   ScienceOn
21 Vasilev, N.P., Julsing, M.K., Koulman, A., Clarkson, C., Woerdenbag, H.J., Ionkova, I., Bos, R., Jaroszewski, J.W., Kayser, O., and Quax, W.J. (2006) Bioconversion of deoxypodophyllotoxin into epipodophyllotoxin in E. coli using human cytochrome P450 3A4. J. Biotechnol. 126, 383-393   DOI   ScienceOn
22 Wong, S.-K., Tsui, S.-K., Kwan, S.-Y., Su, X.-L., and Lin, R.-C. (2000) Identification and characterization of Podophyllum emodi by API-LC/MS/MS. J. Mass Spectrom. 35, 1246-1251   DOI   ScienceOn