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Research ArticleArticle

Monoclonal Antibodies Specific and Inhibitory to Human Cytochromes P450 2C8, 2C9, and 2C19

Kristopher W. Krausz, Inna Goldfarb, Jeroen T. M. Buters, Tian J. Yang, Frank J. Gonzalez and Harry V. Gelboin
Drug Metabolism and Disposition November 2001, 29 (11) 1410-1423;
Kristopher W. Krausz
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Inna Goldfarb
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Jeroen T. M. Buters
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Tian J. Yang
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Frank J. Gonzalez
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Harry V. Gelboin
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Abstract

Hybridomas were isolated that produce 13 monoclonal antibodies (mAbs) that are specific and highly inhibitory to members of the human P450 2C subfamily, 2C8, 2C9, 2C9*2, and 2C19. Many of the mAbs to P450 2C8, 2C9, and 2C19 are specific and exhibit potent inhibitory activity (85–95%). mAb 281-1-1 specifically binds, immunoblots, and strongly inhibits the activity of P450 2C8. mAb 763-15-5 specifically binds and strongly inhibits the activity of P450 2C9. mAb 1-7-4-8 specifically binds and strongly inhibits the activity of P450 2C19. The other mAbs bind and inhibit sets and subsets of the P450 2C family. The single and the combinatorial use of the mAbs can “reaction phenotype”, i.e., determine the metabolic contribution and interindividual variation of a P450 isoform for the metabolism of a drug or nondrug xenobiotic in human liver microsomes. The utility of the mAb-based analytic system was examined with the model substrates Taxol (paclitaxel), diazepam, tolbutamide, diclofenac, mephenytoin, and imipramine. The mAb system can identify drugs metabolized by a common P450 or several P450s and polymorphic P450s. The mAb system identifies drugs or drug metabolic pathways that are catalyzed by a single P450 and thus may be used for in vivo phenotyping. The mAb system can identify whether a particular drug is metabolized by a single P450 that may exhibit polymorphic expression in humans. The mAb system offers large potential for studies of cytochrome P450 function useful in drug discovery and reduces the possibility of adverse drug reactions due to polymorphisms and drug interactions.

Footnotes

  • ↵1 Current address: Institute for Toxicol-GSF, Oberschleisschim, Germany.

  • ↵2 Current address: DuPont Pharmaceuticals Co., Newark, Delaware.

  • ↵4 Requests for monoclonal antibodies from our mAb library should be directed to H. V. Gelboin, National Cancer Institute, National Institutes of Health. The National Institutes of Health Office of Technology Transfer has also arranged for the commercial availability of the mAbs.

  • Abbreviations used are::
    mAb
    monoclonal antibody
    HLM
    human liver microsome
    ELISA
    enzyme-linked immunosorbent assay
    HPLC
    high-performance liquid chromatography
    NDZ
    nordiazepam
    DIM
    desipramine
    RAF
    relative activity factor
    pAb
    polyclonal antibody
    • Received May 8, 2001.
    • Accepted July 20, 2001.
  • U.S. Government
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Drug Metabolism and Disposition: 29 (11)
Drug Metabolism and Disposition
Vol. 29, Issue 11
1 Nov 2001
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Research ArticleArticle

Monoclonal Antibodies Specific and Inhibitory to Human Cytochromes P450 2C8, 2C9, and 2C19

Kristopher W. Krausz, Inna Goldfarb, Jeroen T. M. Buters, Tian J. Yang, Frank J. Gonzalez and Harry V. Gelboin
Drug Metabolism and Disposition November 1, 2001, 29 (11) 1410-1423;

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Research ArticleArticle

Monoclonal Antibodies Specific and Inhibitory to Human Cytochromes P450 2C8, 2C9, and 2C19

Kristopher W. Krausz, Inna Goldfarb, Jeroen T. M. Buters, Tian J. Yang, Frank J. Gonzalez and Harry V. Gelboin
Drug Metabolism and Disposition November 1, 2001, 29 (11) 1410-1423;
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