DOI QR코드

DOI QR Code

Characterization of Deoxypodophyllotoxin Metabolism in Rat Liver Microsomes

  • 발행 : 2008.09.30

초록

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.

키워드

참고문헌

  1. Bogucki, D.E. and Charlton, J.L. (1995) An asymmetric synthesis of (-)-deoxypodophyllotoxin. J. Org. Chem. 60, 588-593 https://doi.org/10.1021/jo00108a021
  2. 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 https://doi.org/10.1055/s-2000-8562
  3. 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 https://doi.org/10.1002/ardp.19943270309
  4. Gross, G. (2001) Clinical diagnosis and management of anogenital warts and papillomavirus-associated lesions. Hautarzt. 52, 6-17 https://doi.org/10.1007/s001050051254
  5. 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 https://doi.org/10.1248/cpb.46.875
  6. 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 https://doi.org/10.1248/cpb.33.704
  7. 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 https://doi.org/10.1248/bpb.31.1312
  8. 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
  9. 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 https://doi.org/10.1055/s-2002-23140
  10. 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 https://doi.org/10.1055/s-2003-42785
  11. 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 https://doi.org/10.1055/s-2003-45110
  12. 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 https://doi.org/10.1055/s-2003-42776
  13. 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 https://doi.org/10.1248/bpb.27.786
  14. 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 https://doi.org/10.1002/rcm.3325
  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 https://doi.org/10.1007/BF02976548
  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 https://doi.org/10.1002/ptr.902
  18. 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 https://doi.org/10.1007/s004250100617
  19. 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 https://doi.org/10.1002/rcm.830
  20. 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 https://doi.org/10.1177/095632029800900307
  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 https://doi.org/10.1016/j.jbiotec.2006.04.025
  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 https://doi.org/10.1002/1096-9888(200011)35:11<1246::AID-JMS55>3.0.CO;2-L

피인용 문헌

  1. In Vivo Suppression of Bisphenol A on Estradiol 2- and 4-Hydroxylase Activities in Hepatic Microsomal Fractions of Male and Female Sprague-Dawley Rats vol.17, pp.2, 2008, https://doi.org/10.4062/biomolther.2009.17.2.188