brucine and Chemical-and-Drug-Induced-Liver-Injury

Brucine (BRU) and brucine N-oxide (BNO) are prominent, bioactive, and toxic alkaloids in crude and processed Semen Strychni. Studies have demonstrated that BRU and BNO possess comprehensive pharmacological activities, such as anti-inflammatory and analgesic. In this context, a comparative study of BRU and BNO was performed by combination analysis of in silico ADMET prediction, in vivo toxicity evaluation, and potential action mechanism exploration. ADMET prediction showed that BRU and BNO might induce liver injury, and BRU may have a stronger hepatoxic effect. The prediction was experimentally verified using the zebrafish model. The BRU-induced hepatotoxicity of zebrafish larvae had a dose-response relationship. The mechanism of BRU-induced hepatotoxicity might relate to phosphorylation, kinase activity, and signal transduction. By comparison, signal transduction and gap junctions might involve BNO-induced hepatotoxicity. Our results provided a better understanding of BRU- and BNO-induced hepatotoxicity. We also built a foundation to elucidate the material base of the hepatotoxicity of traditional Chinese medicine Semen Strychni.

Topics: Animals; Chemical and Drug Induced Liver Injury; Drugs, Chinese Herbal; Strychnine; Zebrafish

Brucine is one of the main bioactive and toxic constituents of the herb drug Semen Strychni. Here we aimed to determine dosing time-dependent hepatotoxicity of brucine, and to investigate the role of metabolism in generation of brucine chronotoxicity. Brucine was administered to wild-type or Npas2

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Basic Helix-Loop-Helix Transcription Factors; Chemical and Drug Induced Liver Injury; Circadian Rhythm; Cytochrome P-450 CYP3A; Drug Chronotherapy; HEK293 Cells; Humans; Liver; Male; Membrane Proteins; Mice, Inbred C57BL; Mice, Knockout; Microsomes, Liver; Nerve Tissue Proteins; Photoperiod; Strychnine