Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon 305-764, South Korea.
Toxicol Lett. 2012 Mar 25;209(3):246-54. doi: 10.1016/j.toxlet.2011.12.017. Epub 2012 Jan 9.
Intestinal microflora (IM) is able to produce toxic and carcinogenic metabolites and induce more potent cytotoxicity against cells than non-metabolites. This study was performed to investigate the cytotoxic responses of geniposide (GS) and its metabolite and to determine the role of metabolism by IM in GS-induced cytotoxicity. Genipin (GP), a GS metabolite, increased cytotoxic effects in cells, but GS did not. Following GS incubation with IM for metabolic activation, increased cytotoxicity was detected compared to GS. Western blot analysis revealed that the activated GS inhibited Bcl-2 expression with a subsequent increase in Bax expression. Likewise, GS activation by IM stimulated caspase-3 and the production of reactive oxygen species (ROS). In addition, activated GS-induced apoptosis was confirmed by apoptosis and ROS assays; N-acetyl-l-cysteine (NAC) suppressed ROS production and apoptotic cell death. Activated GS induced sustained JNK phosphorylation. Moreover, activated GS-induced cell death was reversed by SP600125. Taken together, these findings suggest that human IM is able to metabolize GS into GP, and the related biological activities induce apoptosis through ROS/JNK signaling.
肠道微生物群（IM）能够产生有毒和致癌的代谢物，并对细胞产生比非代谢物更强的细胞毒性。本研究旨在研究京尼平苷（GS）及其代谢物的细胞毒性反应，并确定 IM 代谢在 GS 诱导的细胞毒性中的作用。京尼平（GP），GS 的一种代谢物，增加了细胞的细胞毒性作用，但 GS 没有。GS 与 IM 孵育进行代谢激活后，与 GS 相比，检测到细胞毒性增加。Western blot 分析显示，激活的 GS 抑制 Bcl-2 的表达，随后 Bax 的表达增加。同样，IM 激活 GS 刺激 caspase-3 的产生和活性氧物质（ROS）的产生。此外，通过凋亡和 ROS 测定证实了激活的 GS 诱导的细胞凋亡；N-乙酰-L-半胱氨酸（NAC）抑制 ROS 的产生和凋亡细胞死亡。激活的 GS 诱导 JNK 持续磷酸化。此外，SP600125 逆转了激活的 GS 诱导的细胞死亡。总之，这些发现表明，人肠道微生物群能够将 GS 代谢成 GP，相关的生物学活性通过 ROS/JNK 信号诱导细胞凋亡。
