Interaction of Rhei Rhizoma extract with cytochrome P450 3A and efflux transporters in rats.

Traditional Chinese herbal medicines are frequently prescribed in pharmacotherapy in Japan. In the present study, we evaluated the possible interaction of several herbal extracts including Rhei Rhizoma extract with cytochrome P450 (CYP) 3A and efflux transporters such as P-glycoprotein and multidrug resistance-associated protein (MRP) 2. Rhei Rhizoma extract (100 microg/ml) significantly suppressed the CYP3A-mediated 6beta-hydroxylation of testosterone in hepatic microsomes, and increased the extent of bioavailability of midazolam, a typical CYP3A substrate, in rats. Also, Rhei Rhizoma extract (300 microg/ml) significantly suppressed P-glycoprotein-mediated efflux transport of rhodamine 123 (Rho123) in rat everted intestine. In an in-vivo study, Rhei Rhizoma extract added to intestinal perfusate at a concentration of 300 microg/ml significantly suppressed the intestinal exsorption of Rho123, though it exerted no effect on the biliary excretion of Rho123. Furthermore, the in-vitro and in-vivo MRP2-mediated intestinal efflux of 2,4-dinitrophenyl-S-glutathione was significantly suppressed by Rhei Rhizoma extract (1000 microg/ml). In conclusion, Rhei Rhizoma extract, which is taken orally at doses of 0.5-1 g each or 1-3 g daily in clinical practice, may cause pharmacokinetic herb-drug interactions in the process of the intestinal and/or hepatic CYP3A-mediated drug metabolism and P-glycoprotein- and/or MRP2-mediated efflux transport in the intestine.

Growth-suppressive effect of non-steroidal anti-inflammatory drugs on 11 colon-cancer cell lines and fluorescence differential display of genes whose expression is influenced by sulindac.

In addition to an anti-inflammatory effect, sulindac, one of the non-steroidal anti-inflammatory drugs (NSAIDs), has been shown to have a protective effect against the incidence and mortality of colorectal cancer. However, the molecular basis of its anti-proliferative function remains unclear. To investigate its molecular mechanism, we exposed 11 colon-cancer cell lines to NSAIDs such as aspirin, sulindac and the sulfide and sulfone metabolites of sulindac. Sensitivity to these drugs was dose- and time-dependent but varied from one cell line to another. Among the cell lines examined, sulindac showed a moderate anti-proliferative effect on HT-29 colon cancer cells and caused morphological changes, including an increase of cells with abnormal DNA content. We used the mRNA fluorescence differential display method with these cells to identify molecules that might contribute, through altered expression, to cellular changes in response to NSAIDs. Sixty-eight cDNA fragments were confirmed by RT-PCR to have significantly different expression levels following sulindac treatment. Thirty of these fragments proved to be novel cDNA sequences or identical to expressed sequence tags; the other 38 fragments were identical, or showed significant homology, to genes whose function was already known. Among the known genes differentially expressed in HT-29 cells after sulindac treatment were those encoding acetylglucosaminyltransferase, ferritin heavy chain, zinc finger protein 165, aldose reductase, carcinoembryonic antigen, aldoketoreductase, NF-kappaB-activating kinase, lysosome-associated protein, RhoE = 26 kDa GTPase homologue, NADH oxidoreductase, G/T mismatch bindingprotein, TM7SF3, ADP/ATP carrier-like protein and chromosome segregation protein. This variety among classes of proteins affected by sulindac in our experiments underscores the complexity of anti-proliferative mechanisms that may operate in colon-cancer cells treated with NSAIDs. Furthermore, identification of genes regulated by NSAIDs in colon-cancer cells should provide useful information to identify novel therapeutic targets for treatment and/or prevention of colon cancer.

Isolation and characterization of a human cDNA encoding a protein homologous to the 7.2-kDa protein (subunit X) of bovine ubiquinol-cytochrome C reductase.

Through large-scale sequencing of clones randomly selected from a library of human cDNAs, we have isolated a novel human gene termed hUQCR10. Its open reading frame encodes 63 amino acids that share 88.5% identity with the sequence of bovine ubiquinol-cytochrome C reductase 7.2-kDa protein (subunit X). A single 0.6-kb transcript was expressed in all human tissues examined, but was particularly abundant in heart and skeletal muscle, tissues that consume a large amount of oxygen. The gene product therefore may play a significant role in the cellular respiratory system. In support of this hypothesis, our immunohistochemical analysis revealed that the hUQCR10 protein is located in mitochondria. A homology search using computer programs determined the chromosomal localization of the gene at 22q12.

[Hypervascular liver metastases of gastric cancer completely responding to transcatheter oily chemoembolization using epirubicin hydrochloride, mitomycin C and lipiodol].

A 68-year old woman underwent transarterial oily chemoembolization using Lipiodol with epirubicin hydrochloride and mitomycin C for treatment of multiple hypervascular hepatic metastases of gastric cancer. The tumors showed a good fixation of Lipiodol with a complete biologic response. The tumor has been well controlled for eight months by only one chemoembolization on follow-up study. Transcatheter oily chemoembolization may be an effective treatment not only for hepatocellular carcinoma, but also for hypervascular liver metastases from gastrointestinal malignancies.

[Hepatic metastases from jejunal leiomyosarcoma treated effectively by repeated transarterial embolization with carboplatin].

A 67-year-old man complained of abdominal mass, abdominal pain and tarry stool. He was diagnosed as having jejunal leiomyosarcoma and multiple liver metastases after examination. The jejunal leiomyosarcoma was resected by operation. Unrectable liver metastases were repeatedly treated by transarterial embolization with carboplatin and Lipiodol, and a significant reduction was achieved. TAE with carboplatin and Lipiodol was considered evaluating efficiency therapy without side effect. He has remained well presently for 1 years 10 months after operation.

[Chemoembolization].

Chemoembolization is a technique by which the blood flow in the artery feeding a tumor is arrested and, at the same time, an antitumor agent is delivered in a high concentration to the target site in anticipation of a synergistic antitumor effect. Usually, this is a transcatheter technique. The embolic materials used to arrest the blood flow include gelatin sponge, Lipiodol, microcapsule, albumin microsphere, degradable starch microsphere and the like. Since the gelatin sponge and Lipiodol are available on the market, transcatheter oily chemoembolization (TOCE) using these two materials was performed in cases of hepatic tumor. In many cases of TOCE, adriamycin was used as an adriamycin solution Lipiodol mixture (adriamycin-in-oil emulsion). The cumulative survival rates for 100 patients with unresectable hepatoma treated by TOCE were 53.8% for one year and 36.5% for two years. Thus, improvement was observed in comparison with the cumulative survival rates of 104 patients who underwent hepatic embolization without Lipiodol (1 year, 45.2%, 2 years, 16.3%). Adriamycin-in-oil emulsion retained in the tumor as microemboli brings about the slow-releasing effect of adriamycin. The effect was demonstrated in the blood and tissue concentrations of adriamycin following TOCE.