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Research ArticleArticle

Characterization of Phase I Metabolism of Resibufogenin and Evaluation of the Metabolic Effects on Its Antitumor Activity and Toxicity

Jing Ning, Zhen-Long Yu, Liang-Hai Hu, Chao Wang, Xiao-Kui Huo, Sa Deng, Jie Hou, Jing-Jing Wu, Guang-Bo Ge, Xiao-Chi Ma and Ling Yang
Drug Metabolism and Disposition March 2015, 43 (3) 299-308; DOI: https://doi.org/10.1124/dmd.114.060996
Jing Ning
Research Institute of Integrated Traditional and Western Medicine, College of Pharmacy, Dalian Medical University, Dalian, China (J.N., Z.-L.Y., C.W., X.-K H., S.D., J.H., X.-C.M.); Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, Jilin University, Changchun, China (L.-H., H); Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China (J.N., J.-J.W., G.-B.G., L.Y.); State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (C.W.)
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Zhen-Long Yu
Research Institute of Integrated Traditional and Western Medicine, College of Pharmacy, Dalian Medical University, Dalian, China (J.N., Z.-L.Y., C.W., X.-K H., S.D., J.H., X.-C.M.); Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, Jilin University, Changchun, China (L.-H., H); Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China (J.N., J.-J.W., G.-B.G., L.Y.); State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (C.W.)
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Liang-Hai Hu
Research Institute of Integrated Traditional and Western Medicine, College of Pharmacy, Dalian Medical University, Dalian, China (J.N., Z.-L.Y., C.W., X.-K H., S.D., J.H., X.-C.M.); Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, Jilin University, Changchun, China (L.-H., H); Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China (J.N., J.-J.W., G.-B.G., L.Y.); State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (C.W.)
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Chao Wang
Research Institute of Integrated Traditional and Western Medicine, College of Pharmacy, Dalian Medical University, Dalian, China (J.N., Z.-L.Y., C.W., X.-K H., S.D., J.H., X.-C.M.); Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, Jilin University, Changchun, China (L.-H., H); Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China (J.N., J.-J.W., G.-B.G., L.Y.); State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (C.W.)
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Xiao-Kui Huo
Research Institute of Integrated Traditional and Western Medicine, College of Pharmacy, Dalian Medical University, Dalian, China (J.N., Z.-L.Y., C.W., X.-K H., S.D., J.H., X.-C.M.); Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, Jilin University, Changchun, China (L.-H., H); Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China (J.N., J.-J.W., G.-B.G., L.Y.); State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (C.W.)
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Sa Deng
Research Institute of Integrated Traditional and Western Medicine, College of Pharmacy, Dalian Medical University, Dalian, China (J.N., Z.-L.Y., C.W., X.-K H., S.D., J.H., X.-C.M.); Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, Jilin University, Changchun, China (L.-H., H); Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China (J.N., J.-J.W., G.-B.G., L.Y.); State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (C.W.)
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Jie Hou
Research Institute of Integrated Traditional and Western Medicine, College of Pharmacy, Dalian Medical University, Dalian, China (J.N., Z.-L.Y., C.W., X.-K H., S.D., J.H., X.-C.M.); Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, Jilin University, Changchun, China (L.-H., H); Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China (J.N., J.-J.W., G.-B.G., L.Y.); State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (C.W.)
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Jing-Jing Wu
Research Institute of Integrated Traditional and Western Medicine, College of Pharmacy, Dalian Medical University, Dalian, China (J.N., Z.-L.Y., C.W., X.-K H., S.D., J.H., X.-C.M.); Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, Jilin University, Changchun, China (L.-H., H); Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China (J.N., J.-J.W., G.-B.G., L.Y.); State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (C.W.)
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Guang-Bo Ge
Research Institute of Integrated Traditional and Western Medicine, College of Pharmacy, Dalian Medical University, Dalian, China (J.N., Z.-L.Y., C.W., X.-K H., S.D., J.H., X.-C.M.); Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, Jilin University, Changchun, China (L.-H., H); Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China (J.N., J.-J.W., G.-B.G., L.Y.); State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (C.W.)
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Xiao-Chi Ma
Research Institute of Integrated Traditional and Western Medicine, College of Pharmacy, Dalian Medical University, Dalian, China (J.N., Z.-L.Y., C.W., X.-K H., S.D., J.H., X.-C.M.); Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, Jilin University, Changchun, China (L.-H., H); Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China (J.N., J.-J.W., G.-B.G., L.Y.); State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (C.W.)
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Ling Yang
Research Institute of Integrated Traditional and Western Medicine, College of Pharmacy, Dalian Medical University, Dalian, China (J.N., Z.-L.Y., C.W., X.-K H., S.D., J.H., X.-C.M.); Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, Jilin University, Changchun, China (L.-H., H); Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China (J.N., J.-J.W., G.-B.G., L.Y.); State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (C.W.)
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Abstract

Resibufogenin (RB), one of the major active compounds of the traditional Chinese medicine Chansu, has displayed great potential as a chemotherapeutic agent in oncology. However, it is a digoxin-like compound that also exhibits extremely cardiotoxic effects. The present study aimed to characterize the metabolic behaviors of RB in humans as well as to evaluate the metabolic effects on its bioactivity and toxicity. The phase I metabolic profile in human liver microsomes was characterized systemically, and the major metabolite was identified as marinobufagenin (5β-hydroxylresibufogenin, 5-HRB) by liquid chromatography–mass spectrometry and nuclear magnetic imaging techniques. Both cytochrome P450 (P450) reaction phenotyping and inhibition assays using P450-selective chemical inhibitors demonstrated that CYP3A4 was mainly involved in RB 5β-hydroxylation with much higher selectivity than CYP3A5. Kinetic characterization demonstrated that RB 5β-hydroxylation in both human liver microsomes and human recombinant CYP3A4 obeyed biphasic kinetics and displayed similar apparent kinetic parameters. Furthermore, 5-HRB could significantly induce cell growth inhibition and apoptosis in A549 and H1299 by facilitating apoptosome assembly and caspase activation. Meanwhile, 5-HRB displayed very weak cytotoxicity of human embryonic lung fibroblasts, and in mice there was a greater tolerance to acute toxicity. In summary, CYP3A4 dominantly mediated 5β-hydroxylation and was found to be a major metabolic pathway of RB in the human liver, whereas its major metabolite (5-HRB) displayed better druglikeness than its parent compound RB. Our findings lay a solid foundation for RB metabolism studies in humans and encourage further research on the bioactive metabolite of RB.

Footnotes

    • Received September 8, 2014.
    • Accepted December 11, 2014.
  • J.N. and Z.-L.Y. contributed equally to this work.

  • This work was supported by the National S and T Major Projects of China [Grants 2012ZX09501001, 2012ZX09506001]; and Natural Science Foundation of China [Grants 81274047, 81473334, 81202589, 81302793, and 81202586]; Program for Liaoning Excellent Talents in University [Grant LR2014025]; Liaoning BaiQianWan Talents Program; and Outstanding Youth Science and Technology Talents of Dalian.

  • dx.doi.org/10.1124/dmd.114.060996.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (3)
Drug Metabolism and Disposition
Vol. 43, Issue 3
1 Mar 2015
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Research ArticleArticle

Metabolism of RB and Its Effects on Anticancer Activity

Jing Ning, Zhen-Long Yu, Liang-Hai Hu, Chao Wang, Xiao-Kui Huo, Sa Deng, Jie Hou, Jing-Jing Wu, Guang-Bo Ge, Xiao-Chi Ma and Ling Yang
Drug Metabolism and Disposition March 1, 2015, 43 (3) 299-308; DOI: https://doi.org/10.1124/dmd.114.060996

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Research ArticleArticle

Metabolism of RB and Its Effects on Anticancer Activity

Jing Ning, Zhen-Long Yu, Liang-Hai Hu, Chao Wang, Xiao-Kui Huo, Sa Deng, Jie Hou, Jing-Jing Wu, Guang-Bo Ge, Xiao-Chi Ma and Ling Yang
Drug Metabolism and Disposition March 1, 2015, 43 (3) 299-308; DOI: https://doi.org/10.1124/dmd.114.060996
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