Seneciphylline

Seneciphylline is an orally effective hepatotoxic inducer. Seneciphylline is metabolized by CYP450 enzymes into active intermediates, which covalently bind to intracellular biomacromolecules such as proteins and DNA to form adducts, which in turn trigger a series of toxic reactions, such as inducing cell apoptosis and damaging mitochondrial function. Seneciphylline can be used in hepatotoxicity research. In Vitro:Seneciphylline (10-1000 μM) slightly stimulates rat liver microsomal epoxide hydrolase, has no significant effect on glutathione-S-transferase, and has no significant effect on the activities of aminopyrine demethylase and aryl hydrocarbon hydroxylase (AHH) ^[1].
Seneciphylline (5-50 μM; 6-24 h) reduces the viability of primary mouse and human hepatocytes and induces apoptosis in a time- and dose-dependent manner. Seneciphylline (5-20 μM; 6-12 h) increases the content of pyrrole-protein adducts (PPA) in primary mouse hepatocytes in a time- and dose-dependent manner^[2].
In primary hepatocyte mitochondrial experiments, Seneciphylline (20 μM) induces changes in the morphology of primary mouse hepatocyte mitochondria, making them rounder and shorter, losing mitochondrial membrane potential (MMP)， releasing cytochrome Cyt c from mitochondria to the cytoplasm, and increasing JNK phosphorylation levels^[2].
Seneciphylline (20 μM; 24 hours) -induced apoptosis in primary mouse hepatocytes was effectively inhibited by 50 μM Mdivi-1 (HY-15886) . Mdivi-1 also inhibits Seph-induced mitochondrial depolarization, reduces the number of apoptotic nuclei, reduces the proportion of cells with MMP loss, reduced the level of Cyt c protein in the cytoplasm, and inhibits the cleavage and activation of Caspase-3^[2]. In Vivo:Seneciphylline (70 mg/kg; oral; single dose) can induce severe liver damage in mice, accompanied by inflammation, apoptosis and hepatic sinusoidal hemorrhage. Specifically, serum alanine aminotransferase (ALT)， aspartate aminotransferase (AST)， total bilirubin (TBIL) and total bile acid (TBA) levels were significantly increased, the concentration of pyrrole-protein adducts (PPA) in the liver and serum was increased, and proinflammatory cytokines were increased^[2].