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CYP2J2 and CYP2C19 are the major enzymes responsible for metabolism of albendazole and fenbendazole in human liver microsomes and recombinant P450 assay systems.

Abstract

Albendazole and fenbendazole are broad-spectrum anthelmintics that undergo extensive metabolism to form hydroxyl and sulfoxide metabolites. Although CYP3A and flavin-containing monooxygenase have been implicated in sulfoxide metabolite formation, the enzymes responsible for hydroxyl metabolite formation have not been identified. In this study, we used human liver microsomes and recombinant cytochrome P450s (P450s) to characterize the enzymes involved in the formation of hydroxyalbendazole and hydroxyfenbendazole from albendazole and fenbendazole, respectively. Of the 10 recombinant P450s, CYP2J2 and/or CYP2C19 was the predominant enzyme catalyzing the hydroxylation of albendazole and fenbendazole. Albendazole hydroxylation to hydroxyalbendazole is primarily mediated by CYP2J2 (0.34 μl/min/pmol P450, which is a rate 3.9- and 8.1-fold higher than the rates for CYP2C19 and CYP2E1, respectively), whereas CYP2C19 and CYP2J2 contributed to the formation of hydroxyfenbendazole from fenbendazole (2.68 and 1.94 μl/min/pmol P450 for CYP2C19 and CYP2J2, respectively, which are rates 11.7- and 8.4-fold higher than the rate for CYP2D6). Correlation analysis between the known P450 enzyme activities and the rate of hydroxyalbendazole and hydroxyfenbendazole formation in samples from 14 human liver microsomes showed that albendazole hydroxylation correlates with CYP2J2 activity and fenbendazole hydroxylation correlates with CYP2C19 and CYP2J2 activities. These findings were supported by a P450 isoform-selective inhibition study in human liver microsomes. In conclusion, our data for the first time suggest that albendazole hydroxylation is primarily catalyzed by CYP2J2, whereas fenbendazole hydroxylation is preferentially catalyzed by CYP2C19 and CYP2J2. The present data will be useful in understanding the pharmacokinetics and drug interactions of albendazole and fenbendazole in vivo.

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    College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, South Korea.

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    Source

    Antimicrobial agents and chemotherapy 57:11 2013 Nov pg 5448-56

    MeSH

    Albendazole
    Anthelmintics
    Aryl Hydrocarbon Hydroxylases
    Biotransformation
    Cytochrome P-450 CYP2C19
    Cytochrome P-450 Enzyme Inhibitors
    Cytochrome P-450 Enzyme System
    Enzyme Assays
    Enzyme Inhibitors
    Fenbendazole
    Humans
    Hydroxylation
    Kinetics
    Liver
    Microsomes, Liver
    Recombinant Proteins

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    23959307

    Citation

    Wu, Zhexue, et al. "CYP2J2 and CYP2C19 Are the Major Enzymes Responsible for Metabolism of Albendazole and Fenbendazole in Human Liver Microsomes and Recombinant P450 Assay Systems." Antimicrobial Agents and Chemotherapy, vol. 57, no. 11, 2013, pp. 5448-56.
    Wu Z, Lee D, Joo J, et al. CYP2J2 and CYP2C19 are the major enzymes responsible for metabolism of albendazole and fenbendazole in human liver microsomes and recombinant P450 assay systems. Antimicrob Agents Chemother. 2013;57(11):5448-56.
    Wu, Z., Lee, D., Joo, J., Shin, J. H., Kang, W., Oh, S., ... Liu, K. H. (2013). CYP2J2 and CYP2C19 are the major enzymes responsible for metabolism of albendazole and fenbendazole in human liver microsomes and recombinant P450 assay systems. Antimicrobial Agents and Chemotherapy, 57(11), pp. 5448-56. doi:10.1128/AAC.00843-13.
    Wu Z, et al. CYP2J2 and CYP2C19 Are the Major Enzymes Responsible for Metabolism of Albendazole and Fenbendazole in Human Liver Microsomes and Recombinant P450 Assay Systems. Antimicrob Agents Chemother. 2013;57(11):5448-56. PubMed PMID: 23959307.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - CYP2J2 and CYP2C19 are the major enzymes responsible for metabolism of albendazole and fenbendazole in human liver microsomes and recombinant P450 assay systems. AU - Wu,Zhexue, AU - Lee,Doohyun, AU - Joo,Jeongmin, AU - Shin,Jung-Hoon, AU - Kang,Wonku, AU - Oh,Sangtaek, AU - Lee,Do Yup, AU - Lee,Su-Jun, AU - Yea,Sung Su, AU - Lee,Hye Suk, AU - Lee,Taeho, AU - Liu,Kwang-Hyeon, Y1 - 2013/08/19/ PY - 2013/8/21/entrez PY - 2013/8/21/pubmed PY - 2014/5/16/medline SP - 5448 EP - 56 JF - Antimicrobial agents and chemotherapy JO - Antimicrob. Agents Chemother. VL - 57 IS - 11 N2 - Albendazole and fenbendazole are broad-spectrum anthelmintics that undergo extensive metabolism to form hydroxyl and sulfoxide metabolites. Although CYP3A and flavin-containing monooxygenase have been implicated in sulfoxide metabolite formation, the enzymes responsible for hydroxyl metabolite formation have not been identified. In this study, we used human liver microsomes and recombinant cytochrome P450s (P450s) to characterize the enzymes involved in the formation of hydroxyalbendazole and hydroxyfenbendazole from albendazole and fenbendazole, respectively. Of the 10 recombinant P450s, CYP2J2 and/or CYP2C19 was the predominant enzyme catalyzing the hydroxylation of albendazole and fenbendazole. Albendazole hydroxylation to hydroxyalbendazole is primarily mediated by CYP2J2 (0.34 μl/min/pmol P450, which is a rate 3.9- and 8.1-fold higher than the rates for CYP2C19 and CYP2E1, respectively), whereas CYP2C19 and CYP2J2 contributed to the formation of hydroxyfenbendazole from fenbendazole (2.68 and 1.94 μl/min/pmol P450 for CYP2C19 and CYP2J2, respectively, which are rates 11.7- and 8.4-fold higher than the rate for CYP2D6). Correlation analysis between the known P450 enzyme activities and the rate of hydroxyalbendazole and hydroxyfenbendazole formation in samples from 14 human liver microsomes showed that albendazole hydroxylation correlates with CYP2J2 activity and fenbendazole hydroxylation correlates with CYP2C19 and CYP2J2 activities. These findings were supported by a P450 isoform-selective inhibition study in human liver microsomes. In conclusion, our data for the first time suggest that albendazole hydroxylation is primarily catalyzed by CYP2J2, whereas fenbendazole hydroxylation is preferentially catalyzed by CYP2C19 and CYP2J2. The present data will be useful in understanding the pharmacokinetics and drug interactions of albendazole and fenbendazole in vivo. SN - 1098-6596 UR - https://www.unboundmedicine.com/medline/citation/23959307/CYP2J2_and_CYP2C19_are_the_major_enzymes_responsible_for_metabolism_of_albendazole_and_fenbendazole_in_human_liver_microsomes_and_recombinant_P450_assay_systems_ L2 - http://aac.asm.org/cgi/pmidlookup?view=long&pmid=23959307 DB - PRIME DP - Unbound Medicine ER -