Potential hepatic and renal toxicity induced by the biflavonoids from Ginkgo biloba

Evidence continues to grow on potential health risks associated with Ginkgo biloba and its constituents. While biflavonoid is a subclass of the flavonoid family in Ginkgo biloba with a plenty of pharmacological properties, the potential toxicological effects of biflavonoids remains largely unknown. Thus, the aim of this study was to investigate the in vitro and in vivo toxicological effects of the biflavonoids from Ginkgo biloba (i.e., amentoflavone, sciadopitysin, ginkgetin, isoginkgetin, and bilobetin). In the in vitro cytotoxicity test, the five biflavonoids all reduced cell viability in a dose-dependent manner in human renal tubular epithelial cells (HK-2) and human normal hepatocytes (L-02), indicating they might have potential liver and kidney toxicity. In the in vivo experiments, after intragastrical administration of these biflavonoids at 20 mg·kg^-1·d^-1 for 7 days, serum biochemical analysis and histopathological examinations were performed. The activity of alkaline phosphatase was significantly increased after all the biflavonoid administrations and widespread hydropic degeneration of hepatocytes was observed in ginkgetin or bilobetin-treated mice. Moreover, the five biflavonoids all induced acute kidney injury in treated mice and the main pathological lesions were confirmed to the tubule, glomeruli, and interstitium injuries. As the in vitro and in vivo results suggested that these biflavonoids may be more toxic to the kidney than the liver, we further detected the mechanism of biflavonoids-induced nephrotoxicity. The increased TUNEL-positive cells were detected in kidney tissues of biflavonoids-treated mice, accompanied by elevated expression of proapoptotic protein BAX and unchanged levels of antiapoptotic protein BCL-2, indicating apoptosis was involved in biflavonoids-induced nephrotoxicity. Taken together, our results suggested that the five biflavonoids from Ginkgo biloba may have potential hepatic and renal toxicity and more attentions should be paid to ensure Ginkgo biloba preparations safety.