생명과학회지 (Journal of Life Science)

  • 제23권9호
  • /
  • Pages.1126-1132
  • /
  • 2013
  • /
  • 1225-9918(pISSN)
  • /
  • 2287-3406(eISSN)
한국생명과학회 (Korean Society of Life Science)
권호 표지
DOI QR코드

DOI QR Code

Thelephoric acid의 CYP2J2 효소 활성 저해제 평가

Inhibitory Potential of Thelephoric Acid on CYP2J2 Activities in Human Liver Microsomes

  • 오철학 (경북대학교 약학대학 약학과) ;
  • 이보람 (경북대학교 약학대학 약학과) ;
  • 송경식 (경북대학교 약학대학 약학과) ;
  • 류광현 (경북대학교 약학대학 약학과)
  • Wu, Zhexue (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University) ;
  • Lee, Boram (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University) ;
  • Song, Kyung-Sik (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University) ;
  • Liu, Kwang-Hyeon (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University)
  • 투고 : 2013.09.12
  • 심사 : 2013.09.25
  • 발행 : 2013.09.30
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

CYP2J2 효소는 간외의 조직에 존재 하는 효소로써, 주로 심혈관계에 발현되어 있다. CYP2J2는 내인성 대사체 및 여러 치료 약물들의 대사에 중요한 작용을 하고 있다. 또한 CYP2J2는 인체의 종양조직이나 종양 세포주에서 과발현되어 있어, 종양 치료를 위한 새로운 표적이 되고 있다. 본 연구에서는 천연물 10종을 대상으로 시토크롬 2J2 동효소에 저해능을 가지는 화합물을 발굴하고자 하였다. 10종의 천연물 중 thelephoric acid는 CYP2J2에 의해 매개되는 에바스틴($IC_{50}=5.32{\mu}M$), 아스테미졸($IC_{50}3.23{\mu}M$) 및 터페나딘($IC_{50}=3.27{\mu}M$) 대사를 강력하게 저해하였다. 향후, 이 약물을 대상으로 한 항암 활성 평가가 필요할 것으로 판단된다.

Cytochrome P450 2J2 (CYP2J2) is an enzyme mainly found in human extrahepatic tissues, with predominant expression in the cardiovascular system. CYP2J2 plays important roles in the metabolism of endogenous metabolites and therapeutic drugs, such as arachidonic acid, astemizole, ebastine, and terfenadine. CYP2J2 is also overexpressed in human cancer tissues and cancer cell lines and may represent a potential target for therapy of human cancers. In this study, 10 natural products obtained from plants and microorganisms were screened as potential CYP2J2 inhibitors. Among them, thelephoric acid showed strong inhibition of astemizole O-demethylation activity ($IC_{50}=3.23{\mu}M$) in a dose-dependent manner. Evaluation of the substrate dependency of the inhibitory activity of thelephoric acid showed that it strongly inhibited CYP2J2-mediated ebastine hydroxylation ($IC_{50}=5.32{\mu}M$) and terfenadine hydroxylation ($IC_{50}=3.27{\mu}M$) in a substrate nondependent manner. The present data suggest that this compound might be a potential candidate for further evaluation for anticancer activity.

키워드

참고문헌

  1. Capdevila, J. H., Falck, J. R. and Harris, R. C. 2000. Cytochrome P450 and arachidonic acid bioactivation. Molecular and functional properties of the arachidonate monooxygenase. J Lipid Res 41, 163-181.
  2. Chen, C., Li, G., Liao, W., Wu, J., Liu, L., Ma, D., Zhou, J., Elbekai, R. H., Edin, M. L., Zeldin, D. C. and Wang, D. W. 2009. Selective inhibitors of CYP2J2 related to terfenadine exhibit strong activity against human cancers in vitro and in vivo. J Pharmacol Exp Ther 329, 908-918. https://doi.org/10.1124/jpet.109.152017
  3. Jiang, J. G., Chen, C. L., Card, J. W., Yang, S., Chen, J. X., Fu, X. N., Ning, Y. G., Xiao, X., Zeldin, D. C. and Wang, D. W. 2005. Cytochrome P450 2J2 promotes the neoplastic phenotype of carcinoma cells and is up-regulated in human tumors. Cancer Res 65, 4707-4715. https://doi.org/10.1158/0008-5472.CAN-04-4173
  4. Jiang, J. G., Fu, X. N., Chen, C. L. and Wang, D. W. 2009. Expression of cytochrome P450 arachidonic acid epoxygenase 2J2 in human tumor tissues and cell lines. Ai Zheng 28, 93-96.
  5. Jiang, J. G., Ning, Y. G., Chen, C., Ma, D., Liu, Z. J., Yang, S., Zhou, J., Xiao, X., Zhang, X. A., Edin, M. L., Card, J. W., Wang, J., Zeldin, D. C. and Wang, D. W. 2007. Cytochrome p450 epoxygenase promotes human cancer metastasis. Cancer Res 67, 6665-6674. https://doi.org/10.1158/0008-5472.CAN-06-3643
  6. Lafite, P., Andre, F., Zeldin, D. C., Dansette, P. M. and Mansuy, D. 2007. Unusual regioselectivity and active site topology of human cytochrome P450 2J2. Biochemistry 46, 10237-10247. https://doi.org/10.1021/bi700876a
  7. Lafite, P., Dijols, S., Buisson, D., Macherey, A. C., Zeldin, D. C., Dansette, P. M. and Mansuy, D. 2006. Design and synthesis of selective, high-affinity inhibitors of human cytochrome P450 2J2. Bioorg Med Chem Lett 16, 2777-2780. https://doi.org/10.1016/j.bmcl.2006.02.004
  8. Lee, C. A., Neul, D., Clouser-Roche, A., Dalvie, D., Wester, M. R., Jiang, Y., Jones, J. P., 3rd, Freiwald, S., Zientek, M. and Totah, R. A. 2010. Identification of novel substrates for human cytochrome P450 2J2. Drug Metab Dispos 38, 347-356. https://doi.org/10.1124/dmd.109.030270
  9. Lee, S. S., Jeong, H. E., Liu, K. H., Ryu, J. Y., Moon, T., Yoon, C. N., Oh, S. J., Yun, C. H. and Shin, J. G. 2005. Identification and functional characterization of novel CYP2J2 variants: G312R variant causes loss of enzyme catalytic activity. Pharmacogenet Genomics 15, 105-113. https://doi.org/10.1097/01213011-200502000-00006
  10. Liu, K.-H. 2011. Screening of potential anticancer compounds from marketed drugs: aripiprazole, haloperidol, miconazole, and terfenadine inhibit cytochrome P450 2J2. J Life Sci 21, 1558-1564. https://doi.org/10.5352/JLS.2011.21.11.1558
  11. Liu, K. H., Kim, M. G., Lee, D. J., Yoon, Y. J., Kim, M. J., Shon, J. H., Choi, C. S., Choi, Y. K., Desta, Z. and Shin, J. G. 2006. Characterization of ebastine, hydroxyebastine, and carebastine metabolism by human liver microsomes and expressed cytochrome P450 enzymes: major roles for CYP2J2 and CYP3A. Drug Metab Dispos 34, 1793-1797. https://doi.org/10.1124/dmd.106.010488
  12. Makita, K., Takahashi, K., Karara, A., Jacobson, H. R., Falck, J. R. and Capdevila, J. H. 1994. Experimental and/or genetically controlled alterations of the renal microsomal cytochrome P450 epoxygenase induce hypertension in rats fed a high salt diet. J Clin Invest 94, 2414-2420. https://doi.org/10.1172/JCI117608
  13. Matsumoto, S., Hirama, T., Kim, H. J., Nagata, K. and Yamazoe, Y. 2003. In vitro inhibition of human small intestinal and liver microsomal astemizole O-demethylation: different contribution of CYP2J2 in the small intestine and liver. Xenobiotica 33, 615-623. https://doi.org/10.1080/0049825031000105778
  14. Node, K., Huo, Y., Ruan, X., Yang, B., Spiecker, M., Ley, K., Zeldin, D. C. and Liao, J. K. 1999. Anti-inflammatory properties of cytochrome P450 epoxygenase-derived eicosanoids. Science 285, 1276-1279. https://doi.org/10.1126/science.285.5431.1276
  15. Park, J.-H., Wu, Q., Yoo, K.-H., Yong, H.-I., Cho, S.-M., Chung, I.-S. and Baek, N.-I. 2011. Cytotoxic effect of flavonoids from the roots of glycyrrhiza uralensis on human cancer cell lines. J Appl Biol Chem 54, 67-70. https://doi.org/10.3839/jabc.2011.012
  16. Pfister, S. L. and Campbell, W. B. 1996. Contribution of arachidonic acid metabolites to reduced norepinephrine-induced contractions in hypercholesterolemic rabbit aortas. J Cardiovasc Pharmacol 28, 784-791. https://doi.org/10.1097/00005344-199612000-00008
  17. Pfister, S. L., Spitzbarth, N., Zeldin, D. C., Lafite, P., Mansuy, D. and Campbell, W. B. 2003. Rabbit aorta converts 15-HPETE to trihydroxyeicosatrienoic acids: potential role of cytochrome P450. Arch Biochem Biophys 420, 142-152. https://doi.org/10.1016/j.abb.2003.09.026
  18. Pucci, L., Lucchesi, D., Chirulli, V., Penno, G., Johansson, I., Gervasi, P., Del Prato, S. and Longo, V. 2003. Cytochrome P450 2J2 polymorphism in healthy Caucasians and those with diabetes mellitus. Am J Pharmacogenomics 3, 355-358. https://doi.org/10.2165/00129785-200303050-00006
  19. Scarborough, P. E., Ma, J., Qu, W. and Zeldin, D. C. 1999. P450 subfamily CYP2J and their role in the bioactivation of arachidonic acid in extrahepatic tissues. Drug Metab Rev 31, 205-234. https://doi.org/10.1081/DMR-100101915
  20. Shon, J. H., Yeo, C. W., Liu, K. H., Lee, S. S., Cha, I. J. and Shin, J. G. 2010. Itraconazole and rifampin alter significantly the disposition and antihistamine effect of ebastine and its metabolites in healthy participants. J Clin Pharmacol 50, 195-204. https://doi.org/10.1177/0091270009348974
  21. Sun, J., Sui, X., Bradbury, J. A., Zeldin, D. C., Conte, M. S. and Liao, J. K. 2002. Inhibition of vascular smooth muscle cell migration by cytochrome p450 epoxygenase-derived eicosanoids. Circ Res 90, 1020-1027. https://doi.org/10.1161/01.RES.0000017727.35930.33
  22. Wang, L., Zhang, D., Raghavan, N., Yao, M., Ma, L., Frost, C. E., Maxwell, B. D., Chen, S. Y., He, K., Goosen, T. C., Humphreys, W. G. and Grossman, S. J. 2010. In vitro assessment of metabolic drug-drug interaction potential of apixaban through cytochrome P450 phenotyping, inhibition, and induction studies. Drug Metab Dispos 38, 448-458. https://doi.org/10.1124/dmd.109.029694
  23. Wu, S., Moomaw, C. R., Tomer, K. B., Falck, J. R. and Zeldin, D. C. 1996. Molecular cloning and expression of CYP2J2, a human cytochrome P450 arachidonic acid epoxygenase highly expressed in heart. J Biol Chem 271, 3460-3468. https://doi.org/10.1074/jbc.271.7.3460
  24. Yoon, Y. J. and Liu, K. H. 2011. Potential of hydroxyebastine and terfenadine alcohol to inhibit the human cytochrome P450 2J2 isoform. J Korean Soc Appl Biol Chem 54, 659-666. https://doi.org/10.1007/BF03253143
  25. Yu, Z., Huse, L. M., Adler, P., Graham, L., Ma, J., Zeldin, D. C. and Kroetz, D. L. 2000. Increased CYP2J expression and epoxyeicosatrienoic acid formation in spontaneously hypertensive rat kidney. Mol Pharmacol 57, 1011-1020.
  26. Zeldin, D. C., Foley, J., Boyle, J. E., Moomaw, C. R., Tomer, K. B., Parker, C., Steenbergen, C. and Wu, S. 1997. Predominant expression of an arachidonate epoxygenase in islets of Langerhans cells in human and rat pancreas. Endocrinology 138, 1338-1346. https://doi.org/10.1210/en.138.3.1338

피인용 문헌

  1. Inhibition of cytochrome P450 2J2 by tanshinone IIA induces apoptotic cell death in hepatocellular carcinoma HepG2 cells vol.764, 2015, https://doi.org/10.1016/j.ejphar.2015.07.047
  2. Potential of decursin to inhibit the human cytochrome P450 2J2 isoform vol.70, 2014, https://doi.org/10.1016/j.fct.2014.04.020
  3. Potential of 4′-(p-toluenesulfonylamide)-4-hydroxychalcone to inhibit the human cytochrome P450 2J2 isoform vol.57, pp.1, 2014, https://doi.org/10.1007/s13765-013-4307-y