Psoralen and Isopsoralen, Two Estrogen-Like Natural Products from Psoraleae Fructus, Induced Cholestasis via Activation of ERK1/2
With the increasing use of oral contraceptives and estrogen replacement therapy, the incidence of estrogen-induced cholestasis (EC) has tended to rise. Psoralen (P) and isopsoralen (IP) are the major bioactive components in Psoraleae Fructus, and their estrogen-like activities have already been recognized. Recent studies have also reported that ERK1/2 plays a critical role in EC in mice. This study aimed to investigate whether P and IP induce EC and reveal specific mechanisms. It was found that P and IP increased the expression of esr1, cyp19a1b and the levels of E2 and VTG at 80 μM in zebrafish larvae. Exemestane (Exe), an aromatase antagonist, blocked estrogen-like activities of P and IP. At the same time, P and IP induced cholestatic hepatotoxicity in zebrafish larvae with increasing liver fluorescence areas and bile flow inhibition rates. Further mechanistic analysis revealed that P and IP significantly decreased the expression of bile acids (BAs) synthesis genes cyp7a1 and cyp8b1, BAs transport genes abcb11b and slc10a1, and BAs receptor genes nr1h4 and nr0b2a. In addition, P and IP caused EC by increasing the level of phosphorylation of ERK1/2. The ERK1/2 antagonists GDC0994 and Exe both showed significant rescue effects in terms of cholestatic liver injury. In conclusion, we comprehensively studied the specific mechanisms of P- and IP-induced EC and speculated that ERK1/2 may represent an important therapeutic target for EC induced by phytoestrogens.
Medienart: |
E-Artikel |
---|
Erscheinungsjahr: |
2024 |
---|---|
Erschienen: |
2024 |
Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
---|---|
Enthalten in: |
Chemical research in toxicology - (2024) vom: 22. Apr. |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Chen, Liang-Min [VerfasserIn] |
---|
Links: |
---|
Themen: |
---|
Anmerkungen: |
Date Revised 22.04.2024 published: Print-Electronic Citation Status Publisher |
---|
doi: |
10.1021/acs.chemrestox.4c00054 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
NLM371359570 |
---|
LEADER | 01000naa a22002652 4500 | ||
---|---|---|---|
001 | NLM371359570 | ||
003 | DE-627 | ||
005 | 20240424232318.0 | ||
007 | cr uuu---uuuuu | ||
008 | 240424s2024 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1021/acs.chemrestox.4c00054 |2 doi | |
028 | 5 | 2 | |a pubmed24n1385.xml |
035 | |a (DE-627)NLM371359570 | ||
035 | |a (NLM)38646980 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Chen, Liang-Min |e verfasserin |4 aut | |
245 | 1 | 0 | |a Psoralen and Isopsoralen, Two Estrogen-Like Natural Products from Psoraleae Fructus, Induced Cholestasis via Activation of ERK1/2 |
264 | 1 | |c 2024 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a ƒaComputermedien |b c |2 rdamedia | ||
338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
500 | |a Date Revised 22.04.2024 | ||
500 | |a published: Print-Electronic | ||
500 | |a Citation Status Publisher | ||
520 | |a With the increasing use of oral contraceptives and estrogen replacement therapy, the incidence of estrogen-induced cholestasis (EC) has tended to rise. Psoralen (P) and isopsoralen (IP) are the major bioactive components in Psoraleae Fructus, and their estrogen-like activities have already been recognized. Recent studies have also reported that ERK1/2 plays a critical role in EC in mice. This study aimed to investigate whether P and IP induce EC and reveal specific mechanisms. It was found that P and IP increased the expression of esr1, cyp19a1b and the levels of E2 and VTG at 80 μM in zebrafish larvae. Exemestane (Exe), an aromatase antagonist, blocked estrogen-like activities of P and IP. At the same time, P and IP induced cholestatic hepatotoxicity in zebrafish larvae with increasing liver fluorescence areas and bile flow inhibition rates. Further mechanistic analysis revealed that P and IP significantly decreased the expression of bile acids (BAs) synthesis genes cyp7a1 and cyp8b1, BAs transport genes abcb11b and slc10a1, and BAs receptor genes nr1h4 and nr0b2a. In addition, P and IP caused EC by increasing the level of phosphorylation of ERK1/2. The ERK1/2 antagonists GDC0994 and Exe both showed significant rescue effects in terms of cholestatic liver injury. In conclusion, we comprehensively studied the specific mechanisms of P- and IP-induced EC and speculated that ERK1/2 may represent an important therapeutic target for EC induced by phytoestrogens | ||
650 | 4 | |a Journal Article | |
700 | 1 | |a Qian, Si-Tong |e verfasserin |4 aut | |
700 | 1 | |a Li, Zhuo-Qing |e verfasserin |4 aut | |
700 | 1 | |a He, Ming-Fang |e verfasserin |4 aut | |
700 | 1 | |a Li, Hui-Jun |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t Chemical research in toxicology |d 1989 |g (2024) vom: 22. Apr. |w (DE-627)NLM01260321X |x 1520-5010 |7 nnns |
773 | 1 | 8 | |g year:2024 |g day:22 |g month:04 |
856 | 4 | 0 | |u http://dx.doi.org/10.1021/acs.chemrestox.4c00054 |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |j 2024 |b 22 |c 04 |