Ginkgo biloba extract induces gene expression changes in xenobiotics metabolism and the Myc-centered network.

The use of herbal dietary supplements in the United States is rapidly growing, and it is crucial that the quality and safety of these preparations be ensured. To date, it is still a challenge to determine the mechanisms of toxicity induced by mixtures containing many chemical components, such as herbal dietary supplements. We previously proposed that analyses of the gene expression profiles using microarrays in the livers of rodents treated with herbal dietary supplements is a potentially practical approach for understanding the mechanism of toxicity. In this study, we utilized microarrays to analyze gene expression changes in the livers of male B6C3F1 mice administered Ginkgo biloba leaf extract (GBE) by gavage for 2 years, and to determine pathways and mechanisms associated with GBE treatments. Analysis of 31,802 genes revealed that there were 129, 289, and 2,011 genes significantly changed in the 200, 600, and 2,000 mg/kg treatment groups, respectively, when compared with control animals. Drug metabolizing genes were significantly altered in response to GBE treatments. Pathway and network analyses were applied to investigate the gene relationships, functional clustering, and mechanisms involved in GBE exposure. These analyses indicate alteration in the expression of genes coding for drug metabolizing enzymes, the NRF2-mediated oxidative stress response pathway, and the Myc gene-centered network named "cell cycle, cellular movement, and cancer" were found. These results indicate that Ginkgo biloba-related drug metabolizing enzymes may cause herb-drug interactions and contribute to hepatotoxicity. In addition, the outcomes of pathway and network analysis may be used to elucidate the toxic mechanisms of Ginkgo biloba.

Molecular mechanisms underlying selective cytotoxic activity of BZL101, an extract of Scutellaria barbata, towards breast cancer cells.

We studied the mechanism of the cytotoxic activity of BZL101, an aqueous extract from the herb Scutellaria barbata D. Don, which is currently in phase II clinical trial in patients with advanced breast cancer. The phase I trial showed favorable toxicity profile and promising efficacy. We report here that BZL101 induces cell death in breast cancer cells but not in non-transformed mammary epithelial cells. This selective cytotoxicity is based on strong induction by BZL101 of reactive oxygen species (ROS) in tumor cells. As a consequence, BZL101 treated cancer cells develop extensive oxidative DNA damage and succumb to necrotic death. Data from the expression profiling of cells treated with BZL101 are strongly supportive of a death pathway that involves oxidative stress, DNA damage and activation of death-promoting genes. In breast cancer cells oxidative damage induced by BZL101 leads to the hyperactivation of poly (ADP-ribose) polymerase (PARP), followed by a sustained decrease in levels of NAD and depletion of ATP, neither of which are observed in non-transformed cells. The hyperactivation of PARP is instrumental in the necrotic death program induced by BZL101, because inhibition of PARP results in suppression of necrosis and activation of the apoptotic death program. BZL101 treatment leads to the inhibition of glycolysis selectively in tumor cells, evident from the decrease in the enzymatic activities within the glycolytic pathway and the inhibition of lactate production. Because tumor cells frequently rely on glycolysis for energy production, the observed inhibition of glycolysis is likely a key factor in the energetic collapse and necrotic death that occurs selectively in breast cancer cells. The promising selectivity of BZL101 towards cancer cells is based on metabolic differences between highly glycolytic tumor cells and normal cells.