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Lookup NU author(s): Dr Elaine Mutch, Professor Faith Williams
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Diazinon, chlorpyrifos and parathion are metabolised by multiple cytochromes P450 in human liver. Elaine Mutch and Faith M. Williams 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 (50µM; 500µM) activation to diazoxon, chlorpyrifos (100µM) to chlorpyrifos oxon and parathion (5µM, 20µM, 200µM) 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 (50µM; 500µM) 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. CYP3A and CYP2C8, they also showed that other isoforms can participate in parathion’s metabolism, and may do so when CYP3A and CYP2C8 expression are low. There were significant relationships between paraoxon formation from parathion (5µM, 20µM and 200µM) 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 (100µM). 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.
Author(s): Mutch E, Williams FM
Publication type: Article
Publication status: Published
Journal: Toxicology
Year: 2006
Volume: 224
Issue: 1-2
Pages: 22-32
ISSN (print): 0300-483X
Publisher: Elsevier
URL: http://dx.doi.org/10.1016/j.tox.2006.04.024
DOI: 10.1016/j.tox.2006.04.024
Notes: "Toxicology" has an impact factor of 2.69 (2004), one of the highest in the field of toxicology. The manuscript was recently rejected by Drug Metab Disp (impact factor 3.6) because it had "low relevance" to the audience.
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