title: Diazinon, chlorpyrifos and parathion are metabolised by multiple cytochromes P450 in human liver.
abstract: This research describes both the activation and detoxification of diazinon, chlorpyrifos and parathion by recombinant P450 isozymes and by human liver microsomes that had been characterised for P450 marker activities. Wide variations in activity were found for diazinon (50 microM; 500 microM) activation to diazoxon, chlorpyrifos (100 microM) to chlorpyrifos oxon and parathion (5 microM, 20 microM and 200 microM) to paraoxon in NADPH-dependent reactions. In parallel, the dearylated metabolites pyrimidinol (IHMP), trichloro-2-pyridinol (TCP) and p-nitrophenol (PNP) were produced from diazinon, chlorpyrifos and parathion, respectively, with similarly wide variations in activity. There were significant correlations between diazoxon formation from diazinon (50 microM; 500 microM) with the three CYP3A4/5 marker reactions, while IHMP formation correlated significantly with the three CYP3A4/5 reactions, the CYP2C8 marker reaction (p<0.05) and the CYP2C19 marker (p<0.01). Chlorpyrifos oxon formation from chlorpyrifos did not correlate with any of the P450 markers but TCP formation correlated with one of the CYP3A4/5 reactions (p<0.01) and CYP2C8 (p<0.01), CYP2C19 (p<0.01) and CYP1A2 (p<0.01) mediated reactions. There were significant relationships between paraoxon formation from parathion (5 microM, 20 microM and 200 microM) and the CYP3A4/5, CYP2C8 and CYP1A2 mediated reactions, although only the latter two isoforms correlated significantly with the lowest parathion concentration. Recombinant CYPs 2D6, 2C19, 3A5, 3A4 were most efficient in producing diazoxon and IHMP from diazinon; CYPs 2D6, 3A5, 2B6 and 3A4 were best at producing chlorpyrifos-oxon and CYPs 2C19, 2D6, 3A5 and 3A4 at producing TCP from chlorpyrifos (100 microM). These data strongly suggest that CYPs 3A4/5, 2C8, 1A2, 2C19 and 2D6 are primarily involved in the metabolism of all three OPs, although the profile of participating isoforms was different for each of the pesticides suggesting that chemical structure influences which P450s mediate the reaction. The marked inter-individual variation in expression of the various P450 isozymes may result in sub-populations of individuals that produce higher systemic oxon levels with increased susceptibility to OP toxicity.
authors.affiliation: Toxicology Unit, Devonshire Building, University of Newcastle, Newcastle Upon Tyne NE1 7RU, UK. elaine.mutch@ncl.ac.uk
authors.forename: Elaine
authors.initials: E
authors.lastname: Mutch
authors.forename: Faith M
authors.initials: FM
authors.lastname: Williams
mesh_terms: D004390:Chlorpyrifos / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003976:Diazinon / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D066298:In Vitro Techniques; D007306:Insecticides / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010278:Parathion / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D007306:Insecticides; D007527:Isoenzymes; D011994:Recombinant Proteins; D010278:Parathion; D003577:Cytochrome P-450 Enzyme System; D004390:Chlorpyrifos; D003976:Diazinon