Coordination Mechanism and Bio-Evidence: Reactive γ-Ketoenal Intermediated Hepatotoxicity of Psoralen and Isopsoralen Based on Computer Approach and Bioassay
Abstract
:1. Introduction
2. Results
2.1. MBI Evaluation of Psoralen and Isopsoralen
2.2. Metabolism of Psoralen and Isopsoralen in Liver Microsomes
2.3. Identifying Reactive Metabolites Based on Mechanism-Based Inhibition
2.4. Evidence for Reactive Metabolites-Induced Hepatotoxicity
2.5. Evidence for the Reactive γ-Ketoenal Metabolite–CYP3A4 Heme Fe(II) Coordination Complex
3. Discussion
4. Materials and Methods
4.1. Inhibitory Effects of Psoralen and Isopsoralen on CYP3A4
4.2. MBI Evaluation of Psoralen and Isopsoralen
4.3. Effects of Scavenging Agents (GSH) on Inhibition Ability of Psoralen and Isopsralen
4.4. Metabolism of Psoralen and Isopsoralen in Liver Microsome
4.5. Animals, Treatment, and Sampling
4.6. Molecular Docking Simulation
4.7. Data Analysis
5. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Sample Availability: Not available. |
IC50 (µM) | ||||
---|---|---|---|---|
Enzyme | Compound | (−) NADPH | (+) NADPH | Shift (fold) |
CYP3A4 | Psoralen | >200 | 19.50 ± 1.04 ** | >10.3 |
Isopsoralen | 96.83 ± 2.21 | 9.59 ± 1.04 ** | 10.1 |
Formula | [M + H]+ m/z | Retention Time (min) | Prominent Fragment Ion (m/z) | Peak Area 1 | ||
---|---|---|---|---|---|---|
HLM | MLM | |||||
Psoralen | C11H6O3 | 187 | 7.72 | 159, 143, 131, 115 | ||
M1 | C11H6O4 | 203 | 5.19 | 175.1, 147.0, 119.2 | 557 | 1019 |
M2 | C11H6O4 | 203 | 7.58 | 175.2, 159.1, 147.1, 131.2 | 502 | 8655 |
M3 | C11H6O5 | 219 | 7.23 | 201.1, 174.8, 157.5 | 529 | 164 |
M4 | C11H8O5 | 221 | 3.34 | 203.1, 175.1, 158.9, 147.0 | 66,831 | 98,864 |
M5 | C11H8O5 | 221 | 5.18 | 203.2, 175.1, 147.2 | 61,016 | 102,180 |
Isopsoralen | C11H6O3 | 187 | 8.06 | 158.6, 142.6, 130.6, 114.6 | ||
M′1 | C11H6O4 | 203 | 6.12 | 175.1, 147.0, 119.2 | 1288 | 14,513 |
M′2 | C11H6O4 | 203 | 7.45 | 175.3, 159.0, 147.1, 131.2 | 1349 | 4707 |
M′3 | C11H10O4 | 205 | 5.23 | 177.1,148.8, 133.0, 131.2 | 312 | 418 |
M′4 | C11H8O5 | 221 | 3.80 | 203.3, 174.9, 159.4, 146.8 | 34,274 | 96,828 |
M′5 | C11H8O5 | 221 | 5.01 | 203.3, 175.4 | 1627 | 7725 |
Ligand–Enzyme Complex | −Cdocker Energy | Ligand–Central Ion Distance |
---|---|---|
Psoralen–CYP3A4 | 19.4697 kcal/mol | 3.872 Å |
γ-ketoenal intermediate of psoralen–CYP3A4 | 21.4426 kcal/mol | 2.310 Å |
Furanoepoxide intermediate of psoralen–CYP3A4 | −21.3421 kcal/mol | 6.498 Å |
Isopsoralen–CYP3A4 | 18.5824 kcal/mol | 3.120 Å |
γ-ketoenal intermediate of isopsoralen–CYP3A4 | 19.635 kcal/mol | 2.226 Å |
furanoepoxide intermediate of isopsoralen–CYP3A4 | −23.4627 kcal/mol | 9.993 Å |
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Hai, Y.; Feng, S.; Wang, L.; Ma, Y.; Zhai, Y.; Wu, Z.; Zhang, S.; He, X. Coordination Mechanism and Bio-Evidence: Reactive γ-Ketoenal Intermediated Hepatotoxicity of Psoralen and Isopsoralen Based on Computer Approach and Bioassay. Molecules 2017, 22, 1451. https://doi.org/10.3390/molecules22091451
Hai Y, Feng S, Wang L, Ma Y, Zhai Y, Wu Z, Zhang S, He X. Coordination Mechanism and Bio-Evidence: Reactive γ-Ketoenal Intermediated Hepatotoxicity of Psoralen and Isopsoralen Based on Computer Approach and Bioassay. Molecules. 2017; 22(9):1451. https://doi.org/10.3390/molecules22091451
Chicago/Turabian StyleHai, Yue, Shan Feng, Lili Wang, Yetao Ma, Yiran Zhai, Zijun Wu, Sichao Zhang, and Xin He. 2017. "Coordination Mechanism and Bio-Evidence: Reactive γ-Ketoenal Intermediated Hepatotoxicity of Psoralen and Isopsoralen Based on Computer Approach and Bioassay" Molecules 22, no. 9: 1451. https://doi.org/10.3390/molecules22091451