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Research ArticleArticle

Hepatic Glucuronidation of Isoneochamaejasmin A from the Traditional Chinese Medicine Stellera Chamaejasme L. Root

Lushan Yu, Jianbin Pu, Minjuan Zuo, Xia Zhang, Yang Cao, Shifeng Chen, Yan Lou, Quan Zhou, Haihong Hu, Huidi Jiang, Jianzhong Chen and Su Zeng
Drug Metabolism and Disposition April 2014, 42 (4) 735-743; DOI: https://doi.org/10.1124/dmd.113.055962
Lushan Yu
Department of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China (L.Y., M.Z., X.Z., Y.L., H.H., H.J., S.Z.); Institute of Materia Medica, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China (J.P., Y.C., S.C., J.C.); and Department of Pharmacy, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China (Q.Z.)
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Jianbin Pu
Department of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China (L.Y., M.Z., X.Z., Y.L., H.H., H.J., S.Z.); Institute of Materia Medica, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China (J.P., Y.C., S.C., J.C.); and Department of Pharmacy, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China (Q.Z.)
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Minjuan Zuo
Department of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China (L.Y., M.Z., X.Z., Y.L., H.H., H.J., S.Z.); Institute of Materia Medica, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China (J.P., Y.C., S.C., J.C.); and Department of Pharmacy, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China (Q.Z.)
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Xia Zhang
Department of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China (L.Y., M.Z., X.Z., Y.L., H.H., H.J., S.Z.); Institute of Materia Medica, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China (J.P., Y.C., S.C., J.C.); and Department of Pharmacy, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China (Q.Z.)
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Yang Cao
Department of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China (L.Y., M.Z., X.Z., Y.L., H.H., H.J., S.Z.); Institute of Materia Medica, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China (J.P., Y.C., S.C., J.C.); and Department of Pharmacy, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China (Q.Z.)
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Shifeng Chen
Department of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China (L.Y., M.Z., X.Z., Y.L., H.H., H.J., S.Z.); Institute of Materia Medica, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China (J.P., Y.C., S.C., J.C.); and Department of Pharmacy, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China (Q.Z.)
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Yan Lou
Department of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China (L.Y., M.Z., X.Z., Y.L., H.H., H.J., S.Z.); Institute of Materia Medica, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China (J.P., Y.C., S.C., J.C.); and Department of Pharmacy, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China (Q.Z.)
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Quan Zhou
Department of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China (L.Y., M.Z., X.Z., Y.L., H.H., H.J., S.Z.); Institute of Materia Medica, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China (J.P., Y.C., S.C., J.C.); and Department of Pharmacy, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China (Q.Z.)
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Haihong Hu
Department of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China (L.Y., M.Z., X.Z., Y.L., H.H., H.J., S.Z.); Institute of Materia Medica, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China (J.P., Y.C., S.C., J.C.); and Department of Pharmacy, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China (Q.Z.)
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Huidi Jiang
Department of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China (L.Y., M.Z., X.Z., Y.L., H.H., H.J., S.Z.); Institute of Materia Medica, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China (J.P., Y.C., S.C., J.C.); and Department of Pharmacy, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China (Q.Z.)
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Jianzhong Chen
Department of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China (L.Y., M.Z., X.Z., Y.L., H.H., H.J., S.Z.); Institute of Materia Medica, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China (J.P., Y.C., S.C., J.C.); and Department of Pharmacy, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China (Q.Z.)
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Su Zeng
Department of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China (L.Y., M.Z., X.Z., Y.L., H.H., H.J., S.Z.); Institute of Materia Medica, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China (J.P., Y.C., S.C., J.C.); and Department of Pharmacy, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China (Q.Z.)
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Abstract

Isoneochamaejasmin A (INCA), a biflavonoid, is one of main active ingredients in the dried root of Stellera chamaejasme L., a widely used traditional Chinese medicine. In the present study, we identified the glucuronidation metabolite of INCA and characterized the UDP glucuronosyltransferases (UGTs) responsible for INCA glucuronidation. 7-O-glucuronide (M1) and 4′-O-glucuronide (M2) were identified by incubation of INCA with human liver microsomes (HLMs) in the presence of UDP glucuronic acid, and their structures were confirmed by high-resolution mass spectrometry and nuclear magnetic resonance analyses. Although INCA is a single enantiomer molecule, its M1 metabolite showed two equal-size peaks on a πNAP stationary phase but only one peak on a C18 stationary phase, indicating that the 7-/7′′- and 4′-/4′′′-hydroxyl groups of INCA were in different spatial configurations relative to each other. Among the recombinant human UGT isoform test and correlation analysis, UGT1A1, UGT1A3, and UGT1A9 were found to mediate M1 formation, whereas only UGT1A3 mediated M2 formation. Kinetic studies showed obvious species differences between human, mouse, rat, dog, and pig liver microsomes. UGT1A1, HLMs, and human intestinal microsomes, but not human kidney microsomes, exhibited substrate inhibition for the formation of M1. UGT1A1-mediated formation of M1 showed a 6- and 11-fold higher Vmax than did UGT1A3- and UGT1A9-mediated formation of M1, respectively. The results of the relative activity factor assay showed that UGT1A1 contributed approximately 75% in the formation of M1. These findings collectively indicate that UGT1A1 is the major enzyme in the formation of M1, whereas UGT1A3 is the major enzyme in the formation of M2.

Footnotes

    • Received November 14, 2013.
    • Accepted January 22, 2014.
  • L.Y. and J.P. contributed equally to this work.

  • This research was supported by the Natural Science Foundation of China [Grants 81230080, 81102500, and 81172983]; National Major Projects of China [Grants 2011CB710800 and 2012ZX09506001-004]; and the Zhejiang Natural Science Foundation [LH12H31007].

  • dx.doi.org/10.1124/dmd.113.055962.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 42 (4)
Drug Metabolism and Disposition
Vol. 42, Issue 4
1 Apr 2014
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Research ArticleArticle

UGTs Involved in Isoneochamaejasmin A Metabolism

Lushan Yu, Jianbin Pu, Minjuan Zuo, Xia Zhang, Yang Cao, Shifeng Chen, Yan Lou, Quan Zhou, Haihong Hu, Huidi Jiang, Jianzhong Chen and Su Zeng
Drug Metabolism and Disposition April 1, 2014, 42 (4) 735-743; DOI: https://doi.org/10.1124/dmd.113.055962

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Research ArticleArticle

UGTs Involved in Isoneochamaejasmin A Metabolism

Lushan Yu, Jianbin Pu, Minjuan Zuo, Xia Zhang, Yang Cao, Shifeng Chen, Yan Lou, Quan Zhou, Haihong Hu, Huidi Jiang, Jianzhong Chen and Su Zeng
Drug Metabolism and Disposition April 1, 2014, 42 (4) 735-743; DOI: https://doi.org/10.1124/dmd.113.055962
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