Document Detail


In vitro human metabolism and interactions of repellent N,N-diethyl-m-toluamide.
MedLine Citation:
PMID:  11854147     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Oxidative metabolism of the insect repellent N,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 (K(m)) 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 (Val(374)), 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.
Authors:
Khawja A Usmani; Randy L Rose; Joyce A Goldstein; Wesley G Taylor; Alan A Brimfield; Ernest Hodgson
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Publication Detail:
Type:  Comparative Study; In Vitro; Journal Article; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Drug metabolism and disposition: the biological fate of chemicals     Volume:  30     ISSN:  0090-9556     ISO Abbreviation:  Drug Metab. Dispos.     Publication Date:  2002 Mar 
Date Detail:
Created Date:  2002-02-20     Completed Date:  2002-05-20     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  United States    
Other Details:
Languages:  eng     Pagination:  289-94     Citation Subset:  IM    
Affiliation:
Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina 27695, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Biotransformation
Chlorpyrifos / metabolism,  pharmacology
Chromatography, High Pressure Liquid
Cytochrome P-450 Enzyme System / biosynthesis*,  genetics,  metabolism
DEET / analogs & derivatives,  metabolism*,  pharmacokinetics
Drug Interactions
Enzyme Induction / drug effects
Enzyme Inhibitors / metabolism,  pharmacology
Female
Humans
Insect Repellents / metabolism*,  pharmacokinetics
Isoenzymes / biosynthesis,  genetics,  metabolism
Male
Mice
Microsomes, Liver / enzymology
Oxidation-Reduction
Permethrin / metabolism,  pharmacology
Pyridostigmine Bromide / metabolism,  pharmacology
Rats
Rats, Long-Evans
Spectrometry, Fluorescence
Chemical
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Insect Repellents; 0/Isoenzymes; 0/N,N-diethyl-3-hydroxymethylbenzamide; 0/N-ethyl-3-toluamide; 101-26-8/Pyridostigmine Bromide; 134-62-3/DEET; 2921-88-2/Chlorpyrifos; 52645-53-1/Permethrin; 9035-51-2/Cytochrome P-450 Enzyme System

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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