Biotransformation of geniposide by human intestinal microflora on cytotoxicity against HepG2 cells |
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Authors: | Khanal Tilak Kim Hyung Gyun Choi Jae Ho Do Minh Truong Kong Min Jeong Kang Mi Jeong Noh Kyeumhan Yeo Hee Kyung Ahn Young Tae Kang Wonku Kim Dong Hyun Jeong Tae Cheon Jeong Hye Gwang |
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Affiliation: | a Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon 305-764, South Korea b College of Pharmacy, Yeungnam University, Gyeongsan 712-749, South Korea c College of Pharmacy, Kyung Hee University, Seoul 130-701, South Korea d Department of Food and Nutrition, Kyung Hee University, Seoul 130-701, South Korea e Korea Yakult Co. Ltd., Yongin 446-901, South Korea |
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Abstract: | 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. |
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Keywords: | IM, intestinal microflora GS, geniposide GN, genipin NAC, N-acetyl- smallcaps" >l-cysteine ROS, reactive oxygen species DAPI, 4,6-diamidino-2-phenylindole |
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