Luteolin is a rare substrate of human catechol-O-methyltransferase favoring a para-methylation

Authors

  • Zhong-Jian Chen,

    1. Department of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, P. R. China
    2. Zhejiang Cancer Research Institute, Zhejiang Cancer Hospital, Hangzhou, P. R. China
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  • Yan-Qing Dai,

    1. Department of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, P. R. China
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  • Si-Si Kong,

    1. Department of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, P. R. China
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  • Fei-Feng Song,

    1. Department of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, P. R. China
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  • Li-Ping Li,

    1. Department of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, P. R. China
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  • Jian-Feng Ye,

    1. Department of Research and Development, Conba Pharmaceutical Co. Ltd., Hangzhou, P. R. China
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  • Ru-Wei Wang,

    1. Department of Research and Development, Conba Pharmaceutical Co. Ltd., Hangzhou, P. R. China
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  • Su Zeng,

    1. Department of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, P. R. China
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  • Hui Zhou,

    1. Department of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, P. R. China
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  • Hui-Di Jiang

    Corresponding author
    • Department of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, P. R. China
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Correspondence: Professor Hui-Di Jiang, Department of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, P. R. China

E-mail: hdjiang@zju.edu.cn

Fax: +86-0571-88208408

Abstract

Scope

The study aimed to investigate the regioselectivity of methylation of luteolin (3′,4′,5,7-tetrahydroxyflavone) in human in vitro and in vivo.

Methods and results

Recombinant human catechol-O-methyltransferase (COMT) and human liver S9 were utilized to study the kinetics of meta (3′)- and para (4′)- methylation of luteolin, and urine samples from volunteers after giving a luteolin-containing formulation were collected to determine the ratio of para-/meta-production. The results showed luteolin favored a para-methylation, with a ratio of of para-/meta-production in CLint (1.43 in recombinant human COMT and 1.47 in human liver S9), which was contrary to the known substrates of COMT. However, the result of urine sample assay showed a preference of meta-methylation with a ratio of of para-/meta-production (0.460 ± 0.126). To elucidate the mechanism for different preference of methylation of luteolin in vitro and in vivo, metabolism stability of the meta- and para-methylated luteolin was evaluated in human liver microsomes and recombinant human CYP450s, which revealed that para-methylated luteolin was more easily demethylated by human CYP1A2 and CYP3A4/5 than meta-methylated luteolin.

Conclusion

Luteolin was a rare substrate of human COMT favoring a para-methylation, but further demethylation by human CYP1A2 and CYP3A4/5 caused a preference of accumulation in meta-methylated luteolin in vivo.

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