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Biotransformation and molecular docking of cyazofamid by human liver microsomes and cDNA-expressed human recombinant P450s

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Abstract

The purpose of this study was to understand the formation of metabolites from the metabolic reaction of cyazofamid with human liver microsomes. Human liver microsomal incubation of cyazofamid in the presence of NADPH produced one metabolite, 4-chloro-2-cyano-5-(4-(hydroxymethyl)phenyl)N,N-dimethyl-1H-imidazole-1-sulfonamide (CCHS). An incubation study using cDNA-expressed human recombinant P450s (rCYPs) demonstrated that cyazofamid-derived CCHS is mediated by CYP2B6, 2C9, and 2C19 at different reaction rates. The crystal structure of cyazofamid was obtained using single-crystal X-ray diffraction. According to a molecular modeling study of the crystal structure of cyazofamid with the rCYPs 2B6, 2C9, 2C19, and 3A4, the metabolic reactivities (2B6 > 2C19 > 2C9) were well-correlated to the distances between heme irons of CYPs and 4-methylphenyl group of cyazofamid.

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Acknowledgments

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (NRF-2015M3A9E1028325). The authors thank the Solid State Chemistry Lab of Ajou University (Prof. Hoseop Yun) for X-ray data analysis using RIGAKU R-ASXIS RAPID diffractometer.

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Authors and Affiliations

  1. Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul, 08826, Republic of Korea

    H. Lee, E. Kim, Y. Shin, J.-H. Lee & J.-H. Kim

  2. Geum River Environmental Research Center, National Institute of Environmental Research, Okcheon gun, 29027, Republic of Korea

    H. Lee

  3. College of Pharmacy, The Catholic University of Korea, Bucheon, 14662, Republic of Korea

    J.-H. Kim & H. S. Lee

  4. Division of Bioscience and Biotechnology, BMIC, Konkuk University, Seoul, 05029, Republic of Korea

    H. Jung & Y. Lim

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Correspondence to J.-H. Kim.

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Lee, H., Kim, JH., Kim, E. et al. Biotransformation and molecular docking of cyazofamid by human liver microsomes and cDNA-expressed human recombinant P450s. Appl Biol Chem 59, 649–653 (2016). https://doi.org/10.1007/s13765-016-0204-5

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  • DOI: https://doi.org/10.1007/s13765-016-0204-5

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