Pyrethroid activity-based probes for profiling cytochrome P450 activities associated with insecticide interactions

Hanafy M. Ismail, Paul M. O'Neill, David W. Hong, Robert D. Finn, Colin J. Henderson, Aaron T. Wright, Benjamin F. Cravatt, Janet Hemingway (Lead / Corresponding author), Mark J. I. Paine (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    24 Citations (Scopus)

    Abstract

    Pyrethroid insecticides are used to control diseases spread by arthropods. We have developed a suite of pyrethroid mimetic activity-based probes (PyABPs) to selectively label and identify P450s associated with pyrethroid metabolism. The probes were screened against pyrethroid-metabolizing and nonmetabolizing mosquito P450s, as well as rodent microsomes, to measure labeling specificity, plus cytochrome P450 oxidoreductase and b(5) knockout mouse livers to validate P450 activation and establish the role for b5 in probe activation. Using PyABPs, we were able to profile active enzymes in rat liver microsomes and identify pyrethroid-metabolizing enzymes in the target tissue. These included P450s as well as related detoxification enzymes, notably UDP-glucuronosyltransferases, suggesting a network of associated pyrethroid-metabolizing enzymes, or ``pyrethrome.'' Considering the central role P450s play in metabolizing insecticides, we anticipate that PyABPs will aid in the identification and profiling of P450s associated with insecticide pharmacology in a wide range of species, improving understanding of P450-insecticide interactions and aiding the development of unique tools for disease control.
    Original languageEnglish
    Pages (from-to)19766-19771
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume110
    Issue number49
    DOIs
    Publication statusPublished - 3 Dec 2013

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