title: Biotransformation of geniposide by human intestinal microflora on cytotoxicity against HepG2 cells.
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.
authors.affiliation: Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon 305-764, South Korea.
authors.forename: Tilak
authors.initials: T
authors.lastname: Khanal
authors.forename: Hyung Gyun
authors.initials: HG
authors.lastname: Kim
authors.forename: Jae Ho
authors.initials: JH
authors.lastname: Choi
authors.forename: Minh Truong
authors.initials: MT
authors.lastname: Do
authors.forename: Min Jeong
authors.initials: MJ
authors.lastname: Kong
authors.forename: Mi Jeong
authors.initials: MJ
authors.lastname: Kang
authors.forename: Kyeumhan
authors.initials: K
authors.lastname: Noh
authors.forename: Hee Kyung
authors.initials: HK
authors.lastname: Yeo
authors.forename: Young Tae
authors.initials: YT
authors.lastname: Ahn
authors.forename: Wonku
authors.initials: W
authors.lastname: Kang
authors.forename: Dong Hyun
authors.initials: DH
authors.lastname: Kim
authors.forename: Tae Cheon
authors.initials: TC
authors.lastname: Jeong
authors.forename: Hye Gwang
authors.initials: HG
authors.lastname: Jeong
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001711:Biotransformation; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D005243:Feces / Q000382:microbiology; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D020287:In Situ Nick-End Labeling; D007422:Intestines / Q000382:microbiology*; D039823:Iridoids / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D015394:Molecular Structure; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis
chemical_list: C494826:BAX protein, human; D039823:Iridoids; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; C007835:geniposide; C007834:genipin; D053148:Caspase 3