The Modulatory Role of CYP3A4 in Dictamnine-Induced Hepatotoxicity.

Zhuo-Qing Li,Ping Li,Jing Zhou,Zi-Tian Wu,Xian Zheng,Li-Long Jiang,Dong-Sheng Zhao,Ling-Li Wang,Hui-Jun Li,Zi-Qi Shi

doi:10.3389/fphar.2018.01033

Abstract

Dictamni Cortex (DC) has been reported to be associated with acute hepatitis in clinic and may lead to a selective sub-chronic hepatotoxicity in rats. Nevertheless, the potent toxic ingredient and the underlying mechanism remain unknown. Dictamnine (DTN), the main alkaloid from DC, possesses a furan ring which was suspected of being responsible for hepatotoxicity via metabolic activation primarily by CYP3A4. Herein, the present study aimed to evaluate the role of CYP3A4 in DTN-induced liver injury. The in vitro results showed that the EC50 values in primary human hepatocytes (PHH), L02, HepG2 and NIH3T3 cells were correlated with the CYP3A4 expression levels in corresponding cells. Furthermore, the toxicity was increased in CYP3A4-induced PHH by rifampicin, and CYP3A4 over-expressed (OE) HepG2 and L02 cells. Contrarily, the cytotoxicity was decreased in CYP3A4-inhibited PHH and CYP3A4 OE HepG2 and L02 cells inhibited by ketoconazole (KTZ). In addition, the hepatotoxicity of DTN in enzyme induction/inhibition mice was further investigated in the aspects of biochemistry, histopathology, and pharmacokinetics. Administration of DTN in combination with KTZ resulted in attenuated liver injury, including lower alanine transaminase and aspartate transaminase activities and greater AUC and Cmax of serum DTN, whereas, pretreatment with dexamethasone aggravated the injury. Collectively, our findings illustrated that DTN-induced hepatotoxicity correlated well with the expression of CYP3A4, namely inhibition of CYP3A4 alleviated the toxicity both in vitro and in vivo, and induction aggravated the toxicity effects.

Highlights

There are increasing applications of Chinese herbal medicines (CHMs) for the prevention and treatment of various illnesses, and in parallel, the increased use has been accompanied by an emerging concern regarding the safety of CHMs (Zeng and Jiang, 2010; Willamson et al, 2013; Wang et al, 2015)
Dictamni Cortex (DC, Bai-Xian-Pi in Chinese) (Figure 1A) is the root bark of Dictamnus dasycarpus Turcz. (Family Rutaceae), which is extensively spread throughout China and has been used as a CHM for the treatment of rheumatism, jaundice, skin diseases and chronic hepatitis with a long history (Du et al, 2005; Lv et al, 2015; Chang et al, 2016)
The safety of DC has been questioned as exposure to DC might be associated with the risk of hepatitis in clinic (Blackwell, 1996; Efferth et al, 2017)

Summary

Introduction

There are increasing applications of Chinese herbal medicines (CHMs) for the prevention and treatment of various illnesses, and in parallel, the increased use has been accompanied by an emerging concern regarding the safety of CHMs (Zeng and Jiang, 2010; Willamson et al, 2013; Wang et al, 2015). Cases of severe adverse effects caused by CHMs, hepatotoxicity, have been frequently reported over the past few decades (Teschke et al, 2014; Chan et al, 2015; Coghlan et al, 2015). Several CHMs have been identified as a major cause of drug-induced liver injury, namely herb-induced liver injury (HILI), for example, Polygoni Multiflori Radix (He-Shou-Wu in Chinese) was pointed out to use with caution for the severe hepatotoxicity (Lin et al, 2015; Li H. et al, 2016). (Family Rutaceae), which is extensively spread throughout China and has been used as a CHM for the treatment of rheumatism, jaundice, skin diseases and chronic hepatitis with a long history (Du et al, 2005; Lv et al, 2015; Chang et al, 2016). Chemical studies had been extensively conducted and a large number of compounds, including quinolone alkaloids (Du et al, 2005; Sun et al, 2013), furoquinoline alkaloids (Alkhmedzhanova et al, 1978; Lv et al, 2015) and limonoides (Sun et al, 2015), were isolated in DC, the hepatotoxicity-related causal ingredients remain unidentified so far

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Conclusion