Screening of the Hepatotoxic Components in Fructus Gardeniae and Their Effects on Rat Liver BRL-3A Cells

Abstract

Fructus Gardeniae (FG) is a common Chinese medicine and food. However, the toxicity of FG has drawn increasing concern, especially its hepatotoxicity. The purpose of this study was to screen the hepatotoxic components of FG and evaluate their effects on rat liver BRL-3A cells. The chemical composition of FG was determined by HPLC-ESI-MS. CCK-8 assay was used to evaluate the cytotoxicity of ten chemical components from FG, and then the toxic components with significant inhibitory activity were selected for further study. The results showed that geniposide, genipin, genipin-1-gentiobioside, gardenoside, and shanzhiside all suppress cells viability. Apoptosis assays further indicated that geniposide and its metabolite genipin are the main hepatotoxic components of FG. Pretreatment of cells with geniposide or genipin increased the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP). The activities of superoxide dismutase (SOD) and glutathione (GSH) were decreased, while the malondialdehyde (MDA) level was increased. The cell contents of tumor necrosis factor (TNF-α), interleukin-6 (IL-6), and nitric oxide (NO) were also increased. Molecular docking simulations were used to investigate the mechanism of FG-induced hepatotoxicity, revealing that geniposide and genipin bind strongly to the pro-inflammatory factor TNFR1 receptor of the NF-κB and MAPK signaling pathways. The obtained results strongly indicate that the hepatotoxicity of FG is caused by iridoids compounds. Genipin had the most significant hepatotoxic effect. These toxic substances destroy the cell antioxidant defense system, increasing inflammatory injury to the liver cells and leading to apoptosis and even necrosis. Thus, this study lays a foundation for toxicology research into FG and its rational application.

Effects of Long‐Term Administration of Gardeniae Fructus on Intra‐Abdominal Organs of Rats

“…However, it should be noted that a major GF ingredient, geniposide, has been shown to be acutely hepatotoxic at high doses [23,24]. Possible toxicity of other GF ingredients has also been suggested [25]. In this study, pathological changes such as calcification and fibrosis of the mesenteric vein in the colon were not observed.…”

“…Various pharmacological effects of crocin and crocetin, as well as toxicity, have been reported [31,32]. Pharmacological activity has also been suggested for other GF ingredients, and in vitro studies suggest that many of them may have cytotoxic/hepatotoxic effects [25]. erefore, investigation of GF ingredients and the mechanisms responsible for the pathogenesis of MP warrant further extensive studies.…”

Effects of medicine food Fructus Gardeniae on liver and kidney functions after oral administration to rats for 12 weeks

“…Previous research groups have explored the binding of geniposide and genipin to tumor necrosis factor receptor 1 (TNFR1), an upstream protein of NF‐κB, and mitogen‐activated protein kinase (MAPK) and found that FG constituents can activate related inflammatory pathways (Li et al., 2019). We verified that the expressions of NF‐κBp65, COX‐2, and iNOS in the liver and kidney increase to a certain extent.…”

Toxic Effects of Docosahexaenoic Acid Treatment in the Rat Liver BRL-3A Cell

“…Inflammatory cytokines play a major role during the process of liver inflammation, especially from steatosis to steatohepatitis, or from inflammatory infiltration to liver injury [31]. Previous studies reported that carbohydrates, therapeutic drugs and the hypoxia/reoxygenation model could increase the levels of IL-1 β and IL-6 in the supernatant of BRL-3A cells [13,32,33]. Inflammation interferes with the expression of genes related to lipid metabolism, leading to lipid accumulation [32].…”