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Research ArticleArticle

In Vitro Human Metabolism and Interactions of Repellent N,N-Diethyl-m-Toluamide

Khawja A. Usmani, Randy L. Rose, Joyce A. Goldstein, Wesley G. Taylor, Alan A. Brimfield and Ernest Hodgson
Drug Metabolism and Disposition March 2002, 30 (3) 289-294; DOI: https://doi.org/10.1124/dmd.30.3.289
Khawja A. Usmani
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Randy L. Rose
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Joyce A. Goldstein
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Wesley G. Taylor
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Alan A. Brimfield
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Ernest Hodgson
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Abstract

Oxidative metabolism of the insect repellentN,N-diethyl-m-toluamide (DEET) by pooled human liver microsomes (HLM), rat liver microsomes (RLM), and mouse liver microsomes (MLM) was investigated. DEET is metabolized by cytochromes P450 (P450s) leading to the production of a ring methyl oxidation product,N,N-diethyl-m-hydroxymethylbenzamide (BALC), and an N-deethylated product,N-ethyl-m-toluamide (ET). Both the affinities and intrinsic clearance of HLM for ring hydroxylation are greater than those for N-deethylation. Pooled HLM show significantly lower affinities (Km) than RLM for metabolism of DEET to either of the primary metabolites (BALC and ET). Among 15 cDNA-expressed P450 enzymes examined, CYP1A2, 2B6, 2D6*1 (Val374), and 2E1 metabolized DEET to the BALC metabolite, whereas CYP3A4, 3A5, 2A6, and 2C19 produced the ET metabolite. CYP2B6 is the principal cytochrome P450 involved in the metabolism of DEET to its major BALC metabolite, whereas CYP2C19 had the greatest activity for the formation of the ET metabolite. Use of phenotyped HLMs demonstrated that individuals with high levels of CYP2B6, 3A4, 2C19, and 2A6 have the greatest potential to metabolize DEET. Mice treated with DEET demonstrated induced levels of the CYP2B family, increased hydroxylation, and a 2.4-fold increase in the metabolism of chlorpyrifos to chlorpyrifos-oxon, a potent anticholinesterase. Preincubation of human CYP2B6 with chlorpyrifos completely inhibited the metabolism of DEET. Preincubation of human or rodent microsomes with chlorpyrifos, permethrin, and pyridostigmine bromide alone or in combination can lead to either stimulation or inhibition of DEET metabolism.

Footnotes

  • This research was supported by U.S. Army Cooperative Agreement DAMD 17-00-2-0008. Preliminary studies were presented at the Conference on Illnesses among Gulf War Veterans: A Decade of Scientific Research, Alexandria, Virginia, 2001; and part of the studies will be presented at the 41st Society of Toxicology annual meeting in Nashville, TN, 2002.

  • Abbreviations used are::
    DEET
    N,N-diethyl-m-toluamide
    P450
    cytochrome P450
    BALC
    N,N-diethyl-m-hydroxymethylbenzamide
    ET
    N-ethyl-m-toluamide
    HPLC
    high-performance liquid chromatography
    RLM
    rat liver microsomes
    MLM
    mouse liver microsomes
    HLM
    human liver microsomes
    EROD
    O-deethylation
    MROD
    methoxyresorufinO-demethylation (MROD)
    PROD
    pentoxyresorufinO-dealkylation (PROD)
    BROD
    benzyloxyresorufinO-dealkylation
    • Received September 13, 2001.
    • Accepted December 4, 2001.
  • U.S. Government
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Drug Metabolism and Disposition: 30 (3)
Drug Metabolism and Disposition
Vol. 30, Issue 3
1 Mar 2002
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Research ArticleArticle

In Vitro Human Metabolism and Interactions of Repellent N,N-Diethyl-m-Toluamide

Khawja A. Usmani, Randy L. Rose, Joyce A. Goldstein, Wesley G. Taylor, Alan A. Brimfield and Ernest Hodgson
Drug Metabolism and Disposition March 1, 2002, 30 (3) 289-294; DOI: https://doi.org/10.1124/dmd.30.3.289

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Research ArticleArticle

In Vitro Human Metabolism and Interactions of Repellent N,N-Diethyl-m-Toluamide

Khawja A. Usmani, Randy L. Rose, Joyce A. Goldstein, Wesley G. Taylor, Alan A. Brimfield and Ernest Hodgson
Drug Metabolism and Disposition March 1, 2002, 30 (3) 289-294; DOI: https://doi.org/10.1124/dmd.30.3.289
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