bakuchiol and Chemical-and-Drug-Induced-Liver-Injury

Psoralea corylifolia (P. corylifolia Linn.) is a traditional Chinese medicinal plant that exhibits significant aphrodisiac, diuretic, and anti-rheumatic effects. However, it has been reported to cause hepatic injury, but the precise mechanisms remain unclear.. To evaluate the safety and risk of P. corylifolia and to elucidate the underlying mechanisms of drug-induced liver injury.. Western blotting, enzyme-linked immunosorbent assay (ELISA), immunofluorescence, quantitative polymerase chain reaction (Q-PCR), and flow cytometry were used to explore the effect of bakuchiol (Bak), one of the most abundant and biologically active components of P. corylifolia, on the AIM2 inflammasome activation and the underlying mechanism. Furthermore, we used the lipopolysaccharides (LPS)-induced drug-induced liver injury (DILI) susceptible mice model to study the Bak-mediated hepatotoxicity.. Bak induced the maturation of caspase-1 P20, and significantly increased the expression of IL-1β and TNF-α (P < 0.0001) compared with the control group. Moreover, compared to the Bak group, knockdown of AIM2 inhibited Bak-induced caspase-1 maturation and significantly decreased the production of IL-1β and TNF-α, but knockout of NLRP3 had no effect. Mechanistically, Bak-induced AIM2 inflammasome activation is involved in mitochondrial damage, mitochondrial DNA (mtDNA) release, and subsequent recognition of cytosolic mtDNA. Our in vivo data showed that co-exposure to LPS and non-hepatotoxic doses of Bak significantly increased the levels of ALT, AST, IL-1β, TNF-α, and IL-18, indicating that Bak can induce severe liver inflammation (P < 0.005).. The result shows that Bak activates the AIM2 inflammasome by inducing mitochondrial damage to release mtDNA, and subsequently binds to the AIM2 receptor, indicating that Bak may be a risk factor for P. corylifolia-induced hepatic injury.

Topics: Animals; Caspase 1; Chemical and Drug Induced Liver Injury; DNA-Binding Proteins; DNA, Mitochondrial; Inflammasomes; Interleukin-1beta; Lipopolysaccharides; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; Phenols; Tumor Necrosis Factor-alpha

Psoralea corylifolia L. (Fructus Psoraleae) is widely used in Asia, but there are concerns about hepatotoxicity caused by constituents such as psoralens and bakukiol. Bakuchiol (BAK) has antiinflammatory, antipyretic, antibacterial antiviral, anticancer, and estrogenic activity but appears to be hepatotoxic in in vitro tests. This study investigated the hepatotoxicity in vivo in rats. Using intragastrically administered bakuchiol at doses of 52.5 and 262.5 mg/kg for 6 weeks. Bodyweight, relative liver weight, biochemical indicators, histopathology, mRNA expression of CYP7A1, HMG-CoA reductase, BSEP, PPARα, SREBP-2, and MRP3 were measured. Many abnormalities were observed in the bakuchiol-treated groups including suppression of weight gain and food intake, change of some parameters in serum biochemistry, and increased weight of liver. The mRNA expression of CYP7A1, HMG-CoA reductase, PPARα, and SREBP-2 decreased in bakuchiol-treated group, the expression of BSEP increased in bakuchiol-treated low dosage, and the expression of BSEP decreased in bakuchiol-treated high dosage. In conclusion, we provide evidence for the first time that bakuchiol can induce cholestatic hepatotoxicity, suggesting potential hepatotoxicity. The mechanism may be related to effects on liver lipid metabolism, but further investigation is necessary. Copyright © 2017 John Wiley & Sons, Ltd.

Topics: Animals; Chemical and Drug Induced Liver Injury; Cholestasis; Fabaceae; Fruit; Liver; Male; Molecular Structure; Phenols; Plant Extracts; Psoralea; Rats; Rats, Sprague-Dawley

Liver fibrosis and cirrhosis may be reversible, possibly through the selective clearance of activated hepatic stellate cells/myofibroblasts by apoptosis. Hepatic stellate cells transdifferentiate into myofibroblast-phenotype cells in culture, a process that recapitulates hepatic stellate cell activation in vivo. Bakuchiol, a prenylated phenolic terpene isolated from the seed of Psoralea corylifolia L. (Leguminosae), reduced activated hepatic stellate cells when treated to rats during liver injury recovery period as demonstrated by alpha-smooth muscle actin immunostaining in rat liver and induced apoptosis in activated hepatic stellate cells/myofibroblasts as demonstrated by DNA fragmentation, activation of caspase-3, release of cytochrome c into the cytoplasm, translocation of Bax into mitochondria, and the proteolytic cleavage of poly(ADP-ribose) polymerase (PARP) in vitro. Bakuchiol-induced apoptosis was prevented by z-DEVD-fmk, a specific inhibitor of caspase-3, and z-VAD-fmk, a general caspase inhibitor, suggesting that bakuchiol-induced apoptosis occurs through a caspase-3-dependent pathway in vitro. Bakuchiol treatment stimulated the activation of extracellular signal-regulated kinase 1/2 (ERK), c-Jun NH2-terminal protein kinase (JNK), and p38 mitogen-activated protein kinases (MAPK) in vitro. Pretreatment with SP600125 attenuated the bakuchiol-induced translocation of Bax into mitochondria, cytochrome c release into the cytosol, caspase-3 activation, and PARP cleavage. In contrast, preincubation with SB203580, a p38 MAPK inhibitor, and U0126, an ERK inhibitor, had no effect on bakuchiol-induced cell death and caspase-3 activity. Taken together, these findings indicate that bakuchiol induces caspase-3-dependent apoptosis through the activation of JNK, followed by Bax translocation into mitochondria in rat liver myofibroblasts.

Topics: Actins; Animals; Apoptosis; bcl-2-Associated X Protein; Carbon Tetrachloride; Caspase 3; Cells, Cultured; Chemical and Drug Induced Liver Injury; Cytochromes c; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Activation; Fibroblasts; JNK Mitogen-Activated Protein Kinases; Liver; Liver Diseases; Male; MAP Kinase Signaling System; Mitochondria, Liver; Phenols; Protective Agents; Protein Transport; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Time Factors

The aim of this study was to investigate the protective effect of (S)-bakuchiol isolated from the seed of Psoralea corylifolia, on liver injury. Primary rat hepatocyte intoxication was induced by tert-butyl hydroperoxide (tBH), carbon tetrachloride (CCl4) or D-galactosamine (D-GalN). Liver injury was induced by either CCl4 or D-GalN in rats. In vitro, the cellular leakage of lactate dehydrogenase and cell viability following treatment with hepatotoxicants were significantly improved by bakuchiol treatment at a concentration range of 25-200 microM for tBH, 100-200 microM for CCl4 and 100-200 microM for D-GalN-induced hepatocyte injury. Treatment with bakuchiol significantly inhibited lipid peroxidation and intracellular glutathione depletion in hepatocytes induced by tBH, CCl4 or D-GalN. Treatment with bakuchiol (25 or 50 mg/kg, p.o.) at 1, 24 and 48 h after subcutaneous injection of CCl4 significantly reduced the levels of aspartate transaminase and alanine transaminase in serum. Histological observations revealed that fatty acid changes, hepatocyte necrosis and inflammatory cell infiltration in CCl4-injured liver was improved when treated with bakuchiol. Bakuchiol treatment (25 and 50 mg/kg, p.o.) also significantly reduced the levels of aspartate transaminase and alanine transaminase in an acute liver injury model induced by D-GalN. From these results, bakuchiol has a protective effect against tBH, CCl4 or D-GalN-induced hepatotoxicity in vitro or in vivo.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Galactosamine; Liver; Male; Phenols; Phytotherapy; Plant Extracts; Protective Agents; Psoralea; Rats; Rats, Sprague-Dawley; Seeds; tert-Butylhydroperoxide