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Molecules 2017, 22(9), 1451; doi:10.3390/molecules22091451

Coordination Mechanism and Bio-Evidence: Reactive γ-Ketoenal Intermediated Hepatotoxicity of Psoralen and Isopsoralen Based on Computer Approach and Bioassay

1,†
,
1,2,†
,
1
,
1
,
1
,
1
,
1
and
1,3,*
1
School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Nankai District, Tianjin 300193, China
2
College of Pharmaceutical Sciences and Chinese Medicine, Southwest University, Chongqing 400715, China
3
Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin 300193, China
These authors contributed equally to this manuscript.
*
Author to whom correspondence should be addressed.
Received: 30 July 2017 / Revised: 23 August 2017 / Accepted: 29 August 2017 / Published: 4 September 2017
(This article belongs to the Section Medicinal Chemistry)
View Full-Text   |   Download PDF [23194 KB, uploaded 4 September 2017]   |  

Abstract

Psoralen and isopsoralen are secondary plant metabolites found in many fruits, vegetables, and medicinal herbs. Psoralen-containing plants (Psoralea corylifolia L.) have been reported to cause hepatotoxicity. Herein, we found that psoralen and isopsoralen were oxidized by CYP450s to reactive furanoepoxide or γ-ketoenal intermediates, causing a mechanism-based inhibition of CYP3A4. Furthermore, in GSH-depleted mice, the hepatotoxicity of these reactive metabolites has been demonstrated by pre-treatment with a well-known GSH synthesis inhibitor, L-buthionine-S, Rsulfoxinine (BSO). Moreover, a molecular docking simulation of the present study was undertaken to understand the coordination reaction that plays a significant role in the combination of unstable intermediates and CYP3A4. These results suggested that psoralen and isopsoralen are modest hepatotoxic agents, as their reactive metabolites could be deactivated by H2O and GSH in the liver, which partly contributes to the ingestion of psoralen-containing fruits and vegetables being safe. View Full-Text
Keywords: CYP3A4; γ-ketoenal intermediate; furanoepoxide; molecular docking; coordination compound; GSH depletion; hepatoxicity CYP3A4; γ-ketoenal intermediate; furanoepoxide; molecular docking; coordination compound; GSH depletion; hepatoxicity
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MDPI and ACS Style

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.

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