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http://dx.doi.org/10.5352/JLS.2013.23.9.1126

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

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)
Publication Information
Journal of Life Science / v.23, no.9, 2013 , pp. 1126-1132 More about this Journal
Abstract
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.
Keywords
Thelephoric acid; CYP2J2; screening; drug-interaction; cytochrome P450;
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1 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.   DOI   ScienceOn
2 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.   DOI   ScienceOn
3 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.   DOI   ScienceOn
4 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.   DOI   ScienceOn
5 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.   DOI   ScienceOn
6 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.   DOI
7 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.   DOI
8 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.
9 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.   DOI   ScienceOn
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.   과학기술학회마을   DOI   ScienceOn
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.   DOI   ScienceOn
12 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.   DOI   ScienceOn
13 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.   DOI   ScienceOn
14 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.   DOI   ScienceOn
15 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.   DOI   ScienceOn
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.   DOI
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.   DOI   ScienceOn
18 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.
19 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.   DOI   ScienceOn
20 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.   DOI   ScienceOn
21 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.
22 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.   DOI   ScienceOn
23 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.   DOI   ScienceOn
24 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.   DOI   ScienceOn
25 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.   DOI   ScienceOn
26 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.   DOI   ScienceOn