Abstract
Intestinal microflora (IM) plays a considerable role in the metabolism of endogenous and exogenous substances in the diet, and is thought to have both beneficial and deleterious effects on human health. IM are able to produce toxic or carcinogenic metabolites and induced more potent cytotoxicity against cells than non-metabolites. This study was conducted to investigate the cytotoxic responses of geniposide and its metabolites (genipin) to determine the metabolism of cytotoxic activities. Genipin, geniposide metabolites, increases strong cytotoxic effect in hepatoma cells, but not with geniposide. Western blot analysis revealed that the cleaved-caspase-3 and bax protein significantly increased in a dose-dependent manner after treatment of activated GS for 24 h. However, GS alone did not induce cytotoxicity as well as caspase-3. In addition, activated GS-induced apoptosis was confirmed by apoptosis assays. In this study, GP or activated GS caused reactive oxygen species (ROS) generation and the activated GS-induced cell death was prevented by antioxidants N-acetylcysteine (NAC) suggesting involvement of ROS generation in GP or activated GS-induced cell death. GP or activated GS induced a sustained activation of the phosphorylation of JNK, but not p38 and ERK. Moreover, activated GS-induced cell death was reversed by inhibitor of JNK, but not by p38 or by ERK inhibitor. Taken together, these findings suggest that the human IM is capable to metabolize GS to GP and its related biological activities and induced apoptosis through a ROS/JNK signaling.
