Characterization of human cytochrome P450s involved in the bioactivation of tri-Ortho-Cresyl phosphate (ToCP)
| العنوان: | Characterization of human cytochrome P450s involved in the bioactivation of tri-Ortho-Cresyl phosphate (ToCP) |
|---|---|
| المؤلفون: | Jelle Reinen, Daan Noort, A. Fidder, Leyla Nematollahi, Nico P. E. Vermeulen, Jan N. M. Commandeur |
| المساهمون: | Molecular and Computational Toxicology, AIMMS |
| المصدر: | Reinen, J, Nematollahi, L, Fidder, A, Vermeulen, N P E, Noort, D & Commandeur, J N M 2015, ' Characterization of human cytochrome P450s involved in the bioactivation of tri-Ortho-Cresyl phosphate (ToCP) ', Chemical Research in Toxicology, vol. 28, no. 4, pp. 711-721 . https://doi.org/10.1021/tx500490v Chemical Research in Toxicology, 4 (20 April), 28, 711-721 Chemical Research in Toxicology, 28(4), 711-721. American Chemical Society |
| بيانات النشر: | American Chemical Society, 2015. |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | Cholinesterase inhibition, Unclassified drug, Metabolite, IC50, Pharmacology, Toxicology, Cytochrome P450 3A4, 329736-03-0, Activation, Metabolic, chemistry.chemical_compound, Aerotoxic syndrome, Cytochrome P-450 Enzyme System, Biotransformation, Butyrylcholinesterase, TS - Technical Sciences, Hydrolysis, Enzyme inactivation, Acetylcholinesterase, 9000-81-1, General Medicine, Observation, Weapon & Protection Systems, Acetylcholinesterase, Tritolyl Phosphates, cytochrome P450, 9035-51-2, Biochemistry, Tri ortho cresyl phosphate, 78-30-8, Microsomes, Liver, Liver microsome, Animal cell, Liver microsome metabolism, Cytochrome P450 3A5, 336874-97-6, Cytochrome P450 1A2, Biology, Gas Chromatography-Mass Spectrometry, SDG 3 - Good Health and Well-being, Cytochrome P450 3A4, Cytochrome P450 3A5, Cytochrome P450 2C18, Neurotoxicity, medicine, Animals, Humans, Cholinesterase, 9001-08-5, CYP3A4, human cell, CBRN - CBRN Protection, CYP1A2, In vitro study, Cytochrome P450 2D6, Nonhuman, medicine.disease, Rats, chemistry, Organophosphorus compound, Microsome, Controlled study |
| الوصف: | Tri-ortho-cresyl phosphate (ToCP) is a multipurpose organophosphorus compound that is neurotoxic and suspected to be involved in aerotoxic syndrome in humans. It has been reported that not ToCP itself but a metabolite of ToCP, namely, 2-(ortho-cresyl)-4H-1,2,3-benzodioxaphosphoran-2-one (CBDP), may be responsible for this effect as it can irreversibly bind to human butyrylcholinesterase (BuChE) and human acetylcholinesterase (AChE). The bioactivation of ToCP into CBDP involves Cytochrome P450s (P450s). However, the individual human P450s responsible for this bioactivation have not been identified yet. In the present study, we aimed to investigate the metabolism of ToCP by different P450s and to determine the inhibitory effect of the in vitro generated ToCP-metabolites on human BuChE and AChE. Human liver microsomes, rat liver microsomes, and recombinant human P450s were used for that purpose. The recombinant P450s 2B6, 2C18, 2D6, 3A4 and 3A5 showed highest activity of ToCP-bioactivation to BuChE-inhibitory metabolites. Inhibition experiments using pooled human liver microsomes indicated that P450 3A4 and 3A5 were mainly involved in human hepatic bioactivation of ToCP. In addition, these experiments indicated a minor role for P450 1A2. Formation of CBDP by in-house expressed recombinant human P450s 1A2 and 3A4 was proven by both LC-MS and GC-MS analysis. When ToCP was incubated with P450 1A2 and 3A4 in the presence of human BuChE, CBDP-BuChE-adducts were detected by LC-MS/MS which were not present in the corresponding control incubations. These results confirmed the role of human P450s 1A2 and 3A4 in ToCP metabolism and demonstrated that CBDP is the metabolite responsible for the BuChE inactivation. Interindividual differences at the level of P450 1A2 and 3A4 might play an important role in the susceptibility of humans in developing neurotoxic effects, such as aerotoxic syndrome, after exposure to ToCP. © 2015 American Chemical Society |
| اللغة: | English |
| تدمد: | 0893-228X |
| DOI: | 10.1021/tx500490v |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4eb7a38178e9c163430a723b529b4453 https://doi.org/10.1021/tx500490v |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....4eb7a38178e9c163430a723b529b4453 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 0893228X |
|---|---|
| DOI: | 10.1021/tx500490v |