The Modulatory Role of CYP3A4 in Dictamnine-Induced Hepatotoxicity

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.

In silico Identification and Mechanism Exploration of Hepatotoxic Ingredients in Traditional Chinese Medicine

“…According to in vitro studies, CYP3A4 may play an important role in liver toxicity (Kostrubsky et al, 1995, 1997a,b; Zhang et al, 2010; Zhou et al, 2017, Li et al, 2018). For instance, Dictamnine (DTN), the main alkaloid from a herb called Dictamni Cortex (DC), has been reported to induce liver injury through the regulation of CYP3A4 (Li et al, 2018). The inhibition of CYP3A4 could alleviate the toxicity both in vitro and in vivo while induction of CYP3A4 was able to aggravate the toxicity effects.…”

Metabolic Activation and Hepatotoxicity of Furan-Containing Compounds

“…Cytotoxicity was increased in DEX-induced cells while decreased in KTC-inhibited ones. In addition, KTC pretreatment significantly lowered ALT and AST activities in media, alleviated DIC-induced hepatocyte degeneration and congestion, and DEX caused medium hepatocyte degeneration compared with the slight extent in control groups, suggesting the close relationship between the epoxidation and toxicity (Li et al, 2018).…”

Multi-Omics Integration to Reveal the Mechanism of Hepatotoxicity Induced by Dictamnine

“…Dictamnine is a major furoquinoline alkaloid component in DC which is metabolized into an intermediate epoxide (2,3-epoxide) by CYP3A4 to prevent DC-related HILI ( Li et al, 2018 ; Shi et al, 2019 ). In the present study, pretreatment with KTZ, an inhibitor of the CYP3A4 enzyme, alleviated the hepatotoxicity level induced by dictamnine.…”

“…Verification of dictamnine-induced hepatotoxicity responses: the ICR female mice were randomly assigned into four groups (Con, Dic, KTZ, KTZ/Dic). The experimental procedure followed the protocols previously described by Shi ( Shi et al, 2019 ) and Li ( Li et al, 2018 ) with minor modifications. The mice were pretreated with KTZ in KTZ and KZT/Dic groups (75 mg/kg, intraperitoneally, in 0.5% CMC-Na) 1.5 h before the oral administration of dictamnine (200 mg/kg) for seven consecutive days for the groups Dic and KTZ/Dic.…”