Computational Insight into Biotransformation Profiles of Organophosphorus Flame Retardants to Their Diester Metabolites by Cytochrome P450
Biotransformation of organophosphorus flame retardants (OPFRs) mediated by cytochrome P450 enzymes (CYPs) has a potential correlation with their toxicological effects on humans. In this work, we employed five typical OPFRs including tris(1,3-dichloro-2-propyl) phosphate (TDCIPP), tris(1-chloro-2-pro...
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MDPI AG
2022-04-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/27/9/2799 |
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| author | Yue Jia Tingji Yao Guangcai Ma Qi Xu Xianglong Zhao Hui Ding Xiaoxuan Wei Haiying Yu Zhiguo Wang |
| author_facet | Yue Jia Tingji Yao Guangcai Ma Qi Xu Xianglong Zhao Hui Ding Xiaoxuan Wei Haiying Yu Zhiguo Wang |
| author_sort | Yue Jia |
| collection | DOAJ |
| description | Biotransformation of organophosphorus flame retardants (OPFRs) mediated by cytochrome P450 enzymes (CYPs) has a potential correlation with their toxicological effects on humans. In this work, we employed five typical OPFRs including tris(1,3-dichloro-2-propyl) phosphate (TDCIPP), tris(1-chloro-2-propyl) phosphate (TCIPP), tri(2-chloroethyl) phosphate (TCEP), triethyl phosphate (TEP), and 2-ethylhexyl diphenyl phosphate (EHDPHP), and performed density functional theory (DFT) calculations to clarify the CYP-catalyzed biotransformation of five OPFRs to their diester metabolites. The DFT results show that the reaction mechanism consists of Cα-hydroxylation and O-dealkylation steps, and the biotransformation activities of five OPFRs may follow the order of TCEP ≈ TEP ≈ EHDPHP > TCIPP > TDCIPP. We further performed molecular dynamics (MD) simulations to unravel the binding interactions of five OPFRs in the CYP3A4 isoform. Binding mode analyses demonstrate that CYP3A4-mediated metabolism of TDCIPP, TCIPP, TCEP, and TEP can produce the diester metabolites, while EHDPHP metabolism may generate <i>para</i>-hydroxyEHDPHP as the primary metabolite. Moreover, the EHDPHP and TDCIPP have higher binding potential to CYP3A4 than TCIPP, TCEP, and TEP. This work reports the biotransformation profiles and binding features of five OPFRs in CYP, which can provide meaningful clues for the further studies of the metabolic fates of OPFRs and toxicological effects associated with the relevant metabolites. |
| first_indexed | 2024-03-10T03:54:55Z |
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| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T03:54:55Z |
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| series | Molecules |
| spelling | doaj.art-b7344283032b4275b68f476f07d3f69e2023-11-23T08:49:49ZengMDPI AGMolecules1420-30492022-04-01279279910.3390/molecules27092799Computational Insight into Biotransformation Profiles of Organophosphorus Flame Retardants to Their Diester Metabolites by Cytochrome P450Yue Jia0Tingji Yao1Guangcai Ma2Qi Xu3Xianglong Zhao4Hui Ding5Xiaoxuan Wei6Haiying Yu7Zhiguo Wang8College of Geography and Environmental Sciences, Zhejiang Normal University, Jinhua 321004, ChinaCollege of Geography and Environmental Sciences, Zhejiang Normal University, Jinhua 321004, ChinaCollege of Geography and Environmental Sciences, Zhejiang Normal University, Jinhua 321004, ChinaCollege of Geography and Environmental Sciences, Zhejiang Normal University, Jinhua 321004, ChinaCollege of Geography and Environmental Sciences, Zhejiang Normal University, Jinhua 321004, ChinaCollege of Geography and Environmental Sciences, Zhejiang Normal University, Jinhua 321004, ChinaCollege of Geography and Environmental Sciences, Zhejiang Normal University, Jinhua 321004, ChinaCollege of Geography and Environmental Sciences, Zhejiang Normal University, Jinhua 321004, ChinaInstitute of Ageing Research, School of Medicine, Hangzhou Normal University, Hangzhou 311121, ChinaBiotransformation of organophosphorus flame retardants (OPFRs) mediated by cytochrome P450 enzymes (CYPs) has a potential correlation with their toxicological effects on humans. In this work, we employed five typical OPFRs including tris(1,3-dichloro-2-propyl) phosphate (TDCIPP), tris(1-chloro-2-propyl) phosphate (TCIPP), tri(2-chloroethyl) phosphate (TCEP), triethyl phosphate (TEP), and 2-ethylhexyl diphenyl phosphate (EHDPHP), and performed density functional theory (DFT) calculations to clarify the CYP-catalyzed biotransformation of five OPFRs to their diester metabolites. The DFT results show that the reaction mechanism consists of Cα-hydroxylation and O-dealkylation steps, and the biotransformation activities of five OPFRs may follow the order of TCEP ≈ TEP ≈ EHDPHP > TCIPP > TDCIPP. We further performed molecular dynamics (MD) simulations to unravel the binding interactions of five OPFRs in the CYP3A4 isoform. Binding mode analyses demonstrate that CYP3A4-mediated metabolism of TDCIPP, TCIPP, TCEP, and TEP can produce the diester metabolites, while EHDPHP metabolism may generate <i>para</i>-hydroxyEHDPHP as the primary metabolite. Moreover, the EHDPHP and TDCIPP have higher binding potential to CYP3A4 than TCIPP, TCEP, and TEP. This work reports the biotransformation profiles and binding features of five OPFRs in CYP, which can provide meaningful clues for the further studies of the metabolic fates of OPFRs and toxicological effects associated with the relevant metabolites.https://www.mdpi.com/1420-3049/27/9/2799organophosphorus flame retardantP450 enzymebiotransformationdensity functional theory calculationsmolecular dynamics simulations |
| spellingShingle | Yue Jia Tingji Yao Guangcai Ma Qi Xu Xianglong Zhao Hui Ding Xiaoxuan Wei Haiying Yu Zhiguo Wang Computational Insight into Biotransformation Profiles of Organophosphorus Flame Retardants to Their Diester Metabolites by Cytochrome P450 Molecules organophosphorus flame retardant P450 enzyme biotransformation density functional theory calculations molecular dynamics simulations |
| title | Computational Insight into Biotransformation Profiles of Organophosphorus Flame Retardants to Their Diester Metabolites by Cytochrome P450 |
| title_full | Computational Insight into Biotransformation Profiles of Organophosphorus Flame Retardants to Their Diester Metabolites by Cytochrome P450 |
| title_fullStr | Computational Insight into Biotransformation Profiles of Organophosphorus Flame Retardants to Their Diester Metabolites by Cytochrome P450 |
| title_full_unstemmed | Computational Insight into Biotransformation Profiles of Organophosphorus Flame Retardants to Their Diester Metabolites by Cytochrome P450 |
| title_short | Computational Insight into Biotransformation Profiles of Organophosphorus Flame Retardants to Their Diester Metabolites by Cytochrome P450 |
| title_sort | computational insight into biotransformation profiles of organophosphorus flame retardants to their diester metabolites by cytochrome p450 |
| topic | organophosphorus flame retardant P450 enzyme biotransformation density functional theory calculations molecular dynamics simulations |
| url | https://www.mdpi.com/1420-3049/27/9/2799 |
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