Psoralen Induced Liver Injury by Attenuating Liver Regenerative Capability.

Wang Zhou,Zhenzhou Jiang,Luyong Zhang,Tao Wang,Xi Chen,Dengqiu Xu,Guolin Zhao

doi:10.3389/fphar.2018.01179

Wang Zhou, Zhenzhou Jiang + Show 5 more

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https://doi.org/10.3389/fphar.2018.01179

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Abstract

Psoralen is a major component of the common traditional Chinese medicine Fructus Psoraleae (FP). In this study, we focused on psoralen to explore FP-induced hepatotoxicity and the underlying mechanisms. The acute oral median lethal dose of psoralen in ICR mice was determined to be 1,673 mg/kg. C57BL/6 mice were administered psoralen intragastrically at doses of 400 mg/kg or 800 mg/kg, and were sacrificed 24 h after treatment. Changes in various hepatotoxicity indicators demonstrated that psoralen can cause mild liver injury in mice. Psoralen inhibited the viability of normal human liver L02 cells in vitro by inducing S-phase arrest. In addition, psoralen in both the mouse livers and L02 cells upregulated cyclin E1 and p27 protein levels. The 2/3 partial hepatectomy mouse model was used to further explore the effects of psoralen on the liver regeneration and hepatocellular cycle arrest in vivo. The results showed that the decrease of liver regenerative and self-healing capabilities induced by hepatocellular cycle arrest may play an important role in the hepatotoxicity of psoralen. The further mechanism researches indicated that psoralen-induced hepatotoxicity was associated with inhibition of mTOR signalling pathway and mitochondrial injury; furthermore, MHY, an mTOR activator, partly alleviated the inhibition of mTOR and S-phase cycle arrest induced by psoralen in L02 cells. In conclusion, in this study we showed for the first time, that psoralen significantly induced liver injury in mice; the decrease of liver regenerative and compensatory capabilities induced by hepatocellular cycle arrest may play an important role in the progression of hepatotoxicity associated with the upregulation of cyclin E1 and p27, as well as the inhibition of mTOR signalling and mitochondrial injury. Our findings may contribute to the reduction of hepatotoxicity risk induced by Fructus Psoraleae.

Highlights

Psoralen is a major component of the common traditional Chinese medicinal plant Fructus Psoraleae (FP), the dried matured fruit of the leguminous plant Psoralea corylifolia L. that is widely used in Asian countries, in China and India, for the treatment of osteoporosis, osteomalacia, arthralgia, asthma, vitiligo, and psoriasis (Cheung et al, 2009; Committee, 2015).Psoralen-Induced Hepatotoxicitybased on several clinical reports, FP is associated with severe hepatotoxicity
23 h 44 h, 20 h oral LD50 of psoralen in mice was determined to be 1,673 mg/kg These results showed that psoralen could induce liver injury in body weight
The results indicated that the liver/body weight ratio (Figure 1A) as well as serum alanine aminotransferase (ALT; Figure 1B) and aspartate transaminase (AST) (Figure 1C) levels significantly increased, and serum total protein (TP) (Figure 1D) and ALB (Figure 1E) levels significantly decreased in a dose-dependent manner 24 h after psoralen administration

Summary

Introduction

Psoralen is a major component of the common traditional Chinese medicinal plant Fructus Psoraleae (FP), the dried matured fruit of the leguminous plant Psoralea corylifolia L. that is widely used in Asian countries, in China and India, for the treatment of osteoporosis, osteomalacia, arthralgia, asthma, vitiligo, and psoriasis (Cheung et al, 2009; Committee, 2015).Psoralen-Induced Hepatotoxicitybased on several clinical reports, FP is associated with severe hepatotoxicity. In our previous study, the ethanol (EtOH) extract of FP was shown to induce hepatotoxicity in Sprague-Dawley rats; the chemical constituents of EtOH extract from FP were analysed using HPLC, and the results showed psoralen (21.7 mg/g) and isopsoralen (26.8 mg/g) were the two main components (Wang et al, 2012). Psoralen and its isomer isopsoralen are used as quality control markers of FP according to criteria from the Pharmacopoeia of the People’s Republic of China (Committee, 2015).

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