dicumarol has been researched along with tanshinone* in 2 studies
2 other study(ies) available for dicumarol and tanshinone
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Identification of a novel intestinal first pass metabolic pathway: NQO1 mediated quinone reduction and subsequent glucuronidation.
Quinones represent a very important class of compounds found in nature and for the chemically synthesized drugs. The present study was designed to elucidate the intestinal first pass metabolic pathways in vivo and in vitro, of tanshinone IIA (TS), a derivative of phenanthrene-quinone isolated from Salvia miltiorrhiza. Five metabolites, proposed to be TS catechol glucuronides (two position isomers), dehydrotanshinone IIA and its two catechol glucuronides, were identified from the rat intestinal homogenates after oral administration of TS. TS metabolism was further conducted in the subcellular system including cytosol, microsomes, mitochondrial and S9 under both phase I and phase II metabolic conditions. TS underwent negligible metabolism in all of the subcellular systems under phase I metabolic condition using NADPH as the cofactor. However, significant and substantial metabolic elimination of TS was observed in the cytosol and S9 fractions, while not in the microsomes fractions, when both NADPH and UDPGA were added. Two TS catechol glucuronides were identified from such an in vitro metabolic medium. Dicoumarol, a specific inhibitor of the NAD(P)H dependent quinone oxidoreductase (NQO1), significantly inhibited the metabolic elimination of TS in a noncompetitive way, suggesting that NQO1 was responsible for the quinone reduction of TS to form the catechol intermediate. The catechol intermediate failed to be detected directly was proved to be highly unstable and autoxidized back to TS accompanied with hydrogen peroxide generation. Dicoumarol exhibited a significant inhibitory effect on the hydrogen peroxide generation, further supporting that the reduction of TS was catalyzed by NQO1. The absolute bioavailability of TS was significantly enhanced by oral dicoumarol pretreatment. In conclusion, a novel intestinal metabolic pathway for quinones, NQO1 mediated reduction and subsequent glucuronidation, was determined using TS as a model compound. This study should be helpful for the general understanding of quinones absorption and intestinal first pass metabolism. Topics: Abietanes; Animals; Dicumarol; Drugs, Chinese Herbal; Glucuronides; Intestinal Mucosa; Intestines; Liver; NAD(P)H Dehydrogenase (Quinone); Oxidation-Reduction; Phenanthrenes; Quinones; Rats; Rats, Sprague-Dawley | 2007 |
Tanshinone IIA isolated from Salvia miltiorrhiza elicits the cell death of human endothelial cells.
Tanshinone IIA, a major component extracted from the traditional herbal medicine, Salvia miltiorrhiza Bunge, is known to exhibit potent cytotoxicity against various human carcinoma cells in vitro. However, the mechanism by which tanshinone IIA produces this anti-tumor effect remains unknown. Since anti-neovascularization has generally been regarded as an effective strategy for anti-cancer therapy, we decided to investigate the mechanism underlying tanshinone IIA-mediated death of human endothelial cells. In this study, we demonstrate that tanshinone IIA elicits human endothelial cell death independent of oxidative stress. These events are partially calcium-dependent and actually dependent upon NAD(P)H: quinone oxidoreductase (NQO1) activity. Tanshinone IIA induces an increase in intracellular calcium, which triggers the release of cytochrome c, thus causing loss of the mitochondrial membrane potential (MMP), resulting in the subsequent activation of caspases. Blocking the induction of Ca2+ perturbation with BAPTA-AM partially rescued cells from tanshinone IIA-induced cytotoxicity. Additionally, blocking NQO1 activity with dicoumoral or inhibiting caspase activities with the general caspase inhibitor, z-VAD-fmk, prevented cell death induced by tanshinone IIA. Therefore, our results imply that tanshinone IIA-mediated cytotoxicity against human endothelial cells may occur through activation of NQO1, which induces a calcium imbalance and mitochondrial dysfunction, thus stimulating caspase activity. Topics: Abietanes; Acridine Orange; Amino Acid Chloromethyl Ketones; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Apoptosis; Blotting, Western; Calcium; Caspase Inhibitors; Caspases; Cell Cycle; Cell Death; Cytochromes c; Dicumarol; Drugs, Chinese Herbal; Egtazic Acid; Electrophoresis, Polyacrylamide Gel; Endothelial Cells; Enzyme Activation; Enzyme Inhibitors; Humans; Membrane Potentials; Mitochondria; Models, Biological; NAD(P)H Dehydrogenase (Quinone); Oxidative Stress; Phenanthrenes; Plant Extracts; Reactive Oxygen Species; Salvia miltiorrhiza; Time Factors | 2005 |