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Biotransformation of geniposide by human intestinal microflora on cytotoxicity against HepG2 cells

Tilak Khanal1, Hyung Gyun Kim, Jae Ho Choi

  • 1Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon 305-764, South Korea.

Toxicology Letters
|January 17, 2012
PubMed

Insights

Human gut microbes metabolize geniposide (GS) into genipin (GP), enhancing its cancer-fighting properties. This activated form induces cell death via reactive oxygen species and JNK signaling pathways.

Area of Science:

  • Microbiology
  • Pharmacology
  • Toxicology

Background:

  • Intestinal microflora (IM) produces metabolites with significant cytotoxic and carcinogenic potential.
  • Geniposide (GS) is a compound whose biological activity may be modulated by IM metabolism.
  • Understanding IM's role in metabolizing compounds like GS is crucial for assessing their therapeutic and toxicological profiles.

Purpose of the Study:

  • To investigate the cytotoxic effects of geniposide (GS) and its metabolite, genipin (GP).
  • To determine the influence of intestinal microflora (IM) metabolism on GS-induced cytotoxicity.
  • To elucidate the molecular mechanisms underlying GS metabolism by IM and its subsequent biological activities.

Main Methods:

  • Incubation of GS with IM for metabolic activation.
  • Assessment of cytotoxicity using cell-based assays.
  • Western blot analysis to evaluate protein expression (Bcl-2, Bax, phosphorylated JNK).
  • Measurement of reactive oxygen species (ROS) production and apoptosis.
  • Inhibition studies using N-acetyl-l-cysteine (NAC) and SP600125.

Main Results:

  • Genipin (GP), a GS metabolite, exhibited increased cytotoxicity compared to GS alone.
  • Metabolic activation of GS by IM significantly enhanced its cytotoxic effects.
  • Activated GS modulated apoptosis-related proteins (decreased Bcl-2, increased Bax) and stimulated caspase-3 activity.
  • Activated GS promoted ROS production and induced apoptosis, which were mitigated by NAC.
  • Sustained JNK phosphorylation was observed following activated GS treatment, and cell death was reversed by SP600125.

Conclusions:

  • Human intestinal microflora effectively metabolizes geniposide (GS) into genipin (GP).
  • The metabolite genipin (GP) is responsible for the observed cytotoxic effects.
  • GS metabolism by IM induces apoptosis through the ROS/JNK signaling pathway.
  • These findings highlight the critical role of microbial metabolism in determining the biological activity of geniposide.

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