title: In vitro human metabolism and interactions of repellent N,N-diethyl-m-toluamide.
abstract: 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.affiliation: Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina 27695, USA.
authors.forename: Khawja A
authors.initials: KA
authors.lastname: Usmani
authors.forename: Randy L
authors.initials: RL
authors.lastname: Rose
authors.forename: Joyce A
authors.initials: JA
authors.lastname: Goldstein
authors.forename: Wesley G
authors.initials: WG
authors.lastname: Taylor
authors.forename: Alan A
authors.initials: AA
authors.lastname: Brimfield
authors.forename: Ernest
authors.initials: E
authors.lastname: Hodgson
mesh_terms: D000818:Animals; D001711:Biotransformation; D004390:Chlorpyrifos / Q000378:metabolism / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D003671:DEET / Q000031:analogs & derivatives / Q000378:metabolism* / Q000493:pharmacokinetics; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007302:Insect Repellents / Q000378:metabolism* / Q000493:pharmacokinetics; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology; D010084:Oxidation-Reduction; D026023:Permethrin / Q000378:metabolism / Q000494:pharmacology; D011729:Pyridostigmine Bromide / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D013050:Spectrometry, Fluorescence
chemical_list: D004791:Enzyme Inhibitors; D007302:Insect Repellents; D007527:Isoenzymes; C454677:N,N-diethyl-3-hydroxymethylbenzamide; C454678:N-ethyl-3-toluamide; D003671:DEET; D026023:Permethrin; D003577:Cytochrome P-450 Enzyme System; D004390:Chlorpyrifos; D011729:Pyridostigmine Bromide