Abass, K., Reponen, P., Alsanie, W. F., Rautio, A., & Pelkonen, O. (2022). Characterization of furathiocarb metabolism in in-vitro human liver microsomes and recombinant cytochrome P450 enzymes. Toxicology Reports, 9, 679–689. https://doi.org/10.1016/j.toxrep.2022.03.046
Characterization of furathiocarb metabolism in in-vitro human liver microsomes and recombinant cytochrome P450 enzymes
|Author:||Abass, Khaled1,1,1; Reponen, Petri2; Alsanie, Walaa F.3;|
1Arctic Health, Faculty of Medicine, University of Oulu, P.O. Box 7300, FI-90014, Finland
2Pharmacology and Toxicology Unit, Research Unit of Biomedicine, University of Oulu, P.O. Box 5000, Oulu FI-90014, Finland
3Department of Clinical Laboratory Sciences, The Faculty of Applied Medical Sciences & Centre of Biomedical Sciences Research (CBSR), Taif University, Saudi Arabia
4Thule Institute, University of the Arctic, Oulu FI-90014, Finland
|Online Access:||PDF Full Text (PDF, 3.3 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2022101762225
|Publish Date:|| 2022-10-17
Furathiocarb is a carbamate insecticide detected in ecosystems. Its main metabolite carbofuran has been alluded to affect birth outcomes and disturb hormone levels in humans. The metabolism of furathiocarb in humans has not been characterized. The metabolism studies were performed using hepatic microsomes from ten donors and fifteen human cDNA-expressed CYPs. The initial screening and identification of the metabolites were performed by LC-TOF. Quantiﬁcations and fragmentations were performed by LC/MS-MS. Furathiocarb was metabolized to eight phase I metabolites via two general pathways, carbofuran metabolic pathway and furathiocarb oxidation pathway. Six metabolites in the carbofuran metabolic pathway (carbofuran, 3-hydroxycarbofuran, 3-ketocarbofuran, 3-keto-7-phenolcarbofuran, 3-hydroxy-7-phenolcarbofuran, and 7-phenolcarbofuran) were identified with the help of authentic standards. The two unidentiﬁed metabolites in the furathiocarb oxidation pathway are probably hydroxylated and sulfoxidated derivatives of furathiocarb. The carbofuran metabolic pathway was more predominant than the furathiocarb oxidation pathway, ratios ranged from 24- to 115-fold in a 10-donor panel of hepatic microsomes. On the basis of recombinant CYP studies, the carbofuran pathway was dominated by CYP3A4 (95.9%); contributions by CYP1A2 (1.3%) and CYP2B6 (2.0%) were minor. The minor furathiocarb oxidation pathway was catalyzed by CYP2C19 and CYP2D6 (hydroxylated/sulfoxidated metabolite A) and by CYP3A5, CYP3A4 and CYP2A6 (metabolite B). High and significant correlation between carbofuran metabolic pathway and CYP3A4 marker activities (midazolam-1’-hydroxylation and omeprazole-sulfoxidation) were observed. Ketoconazole, a CYP3A4-inhibitor, inhibited the carbofuran pathway by 32–86% and hydroxylated/sulfoxidated metabolite-B formations by 41–62%. The data suggest that in humans, the carbofuran metabolic pathway is dominant, and CYP3A4 is the major enzyme involved. These results provide useful scientific information for furathiocarb risk assessment in humans.
|Pages:||679 - 689|
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
This research was supported by the European Union's Horizon 2020 program EDCMET (grant number 825762). Walaa F. Alsanie would like to acknowledge Taif University for support No. TURSP (2020/53).
|EU Grant Number:||
(825762) EDCMET - Metabolic effects of Endocrine Disrupting Chemicals: novel testing METhods and adverse outcome pathways
Supplementary data associated with this article can be found in the online version at doi:10.1016/j.toxrep.2022.03.046.
© 2022 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).