1. Phosmet bioactivation by isoform-specific cytochrome P450s in human hepatic and gut samples and metabolic interaction with chlorpyrifos.
- Author
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Santori N, Buratti FM, Dorne JCM, and Testai E
- Subjects
- Chlorpyrifos chemistry, Chlorpyrifos metabolism, Cytochrome P-450 Enzyme System genetics, Drug Interactions, Gene Expression Regulation, Enzymologic drug effects, Humans, Insecticides chemistry, Insecticides metabolism, Insecticides pharmacokinetics, Isoenzymes, Liver enzymology, Molecular Structure, Phosmet chemistry, Phosmet metabolism, Risk Assessment, Chlorpyrifos toxicity, Cytochrome P-450 Enzyme System metabolism, Insecticides toxicity, Phosmet toxicity
- Abstract
Data on the bioactivation of Phosmet (Pho), a phthalimide-derived organophosphate pesticide (OPT), to the neurotoxic metabolite Phosmet-oxon (PhOx) in human are not available. The characterization of the reaction in single human recombinant CYPs evidenced that the ranking of the intrinsic clearances was: 2C18>2C19>2B6>2C9>1A1>1A2>2D6>3A4>2A6. Considering the average human hepatic content, CYP2C19 contributed for the great majority (60%) at relevant exposure concentrations, while CYP2C9 (33%) and CYP3A4 (31%) were relevant at high substrate concentration. The dose-dependent role of the active isoforms was confirmed in human liver microsomes by using selective CYP inhibitors. This prominent role of CYP2C in oxon formation was not shared by other OPTs. The pre-systemic Pho bioactivation measured in human intestinal microsomes was relevant accounting for ¼ of that measured in the liver showing two reaction phases catalysed by CYP2C and CYP3A4. Phosmet efficiently inhibited CPF bioactivation and detoxication, with Ki values (≈30 μM) relevant to pesticide concentrations achievable in the human liver, while the opposite is unlikely (Ki ≈ 160 μM) at the actual exposure levels, depending on the peculiar isoform-specific Pho bioactivation. Kinetic information in humans can support the development of quantitative in vitro/in vivo extrapolation and in silico models for risk assessment refinement for single and multiple pesticides., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Published
- 2020
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