Characterization of 1'-hydroxymidazolam glucuronidation in human liver microsomes.
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Midazolam is a potent benzodiazepine derivative with sedative, hypnotic, anticonvulsant, muscle-relaxant, and anxiolytic activities. It undergoes oxidative metabolism catalyzed almost exclusively by the CYP3A subfamily to a major metabolite, 1'-hydroxymidazolam, which is equipotent to midazolam. 1'-Hydroxymidazolam is subject to glucuronidation followed by renal excretion. To date, the glucuronidation of 1'-hydroxymidazolam has not been evaluated in detail. In the current study, we identified an unreported quaternary N-glucuronide, as well as the known O-glucuronide, from incubations of 1'-hydroxymidazolam in human liver microsomes enriched with uridine 5'-diphosphoglucuronic acid (UDPGA). The structure of the N-glucuronide was confirmed by nuclear magnetic resonance analysis, which showed that glucuronidation had occurred at N-2 (the imidazole nitrogen that is not a part of the benzodiazepine ring). In a separate study, in which midazolam was used as the substrate, an analogous N-glucuronide also was detected from incubations with human liver microsomes in the presence of UDPGA. Investigation of the kinetics of 1'-hydroxymidazolam glucuronidation in human liver microsomes indicated autoactivation kinetics (Hill coefficient, n = 1.2-1.5). The apparent S(50) values for the formation of O- and N-glucuronides were 43 and 18 microM, respectively, and the corresponding apparent V(max) values were 363 and 21 pmol/mg of microsomal protein/min. Incubations with recombinant human uridine diphosphate glucuronosyltransferases (UGTs) indicated that the O-glucuronidation was catalyzed by UGT2B4 and UGT2B7, whereas the N-glucuronidation was catalyzed by UGT1A4. Consistent with these observations, hecogenin, a selective inhibitor of UGT1A4, selectively inhibited the N-glucuronidation, whereas diclofenac, a potent inhibitor of UGT2B7, had a greater inhibitory effect on the O-glucuronidation than on the N-glucuronidation. In summary, our study provides the first demonstration of N-glucuronidation of 1'-hydroxymidazolam in human liver microsomes. (+info)
20(S)-25-methoxyl-dammarane-3beta, 12beta, 20-triol, a novel natural product for prostate cancer therapy: activity in vitro and in vivo and mechanisms of action.
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Conversion of esculeoside A into esculeogenin B.
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Conversion of the spirosolane-type glycoside, esculeoside A, a major component contained in the ripe tomato Lycopersicon esculentum fruits, into a solanocapsine-type sapogenol, esculeogenin B-2, (5alpha,22S,23R,25S)-22,26-epimino-16beta,23-epoxy-3beta,23,27-trihydroxycholesta ne, and esculeogenin B-1, (5alpha,22R,23S,25S)-22,26-epimino-16beta,23-epoxy-3beta,23,27-trihydroxycholesta ne, which are rare naturally occurring compounds was attained by acid hydrolysis with 2 N HCl in dioxane and water (1 : 1). (+info)
Mechanism for conversion of spirosolane derivative into pregnane.
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Previously, we reported an interesting reaction by which esculeogenin A [(5alpha,22S,23S,25S)-3beta,23,27-trihydroxyspirosolane], a sapogenol of tomato-saponin, esculeoside A, was easily converted into a pregnane derivative, 5alpha-pregn-16-en-3beta-ol-20-one, merely by refluxing with pyridine and water. Its chemical mechanism including air oxidation is here described. (+info)
The effects of saikosaponin-d on yeast phagocytosis and degradation in peritoneal macrophages: related increase in Fc receptor expression and altered cytoplasmic organization.
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The effects of saikosaponin-d (ssd), isolated from Bupleurum radix, on phagocytic functions of mouse peritoneal macrophages were investigated in macrophage cultures after treatment in vivo. We also compared the ultrastructural appearances of macrophages from ssd-treated mice with those from control mice. The macrophages from ssd-treated mice showed a significant increase in phagocytosis, intracellular killing of yeast and acid phosphatase activity. Treatment of mice with ssd also induced the Fc receptor expression in macrophages. The macrophages from ssd-treated mice showed more intense spreading on a glass surface than those from the control mice after a 60 min-incubation. Furthermore, the macrophages from ssd-treated mice seemed to possess a well-developed Golgi apparatus and the large vacuoles. The data suggest that the functional changes in the macrophages from ssd-treated mice are brought about by a modification in the surface membrane and the intracellular distribution. (+info)
Telomerase-based pharmacologic enhancement of antiviral function of human CD8+ T lymphocytes.
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Telomerase reverse transcribes telomere DNA onto the ends of linear chromosomes and retards cellular aging. In contrast to most normal somatic cells, which show little or no telomerase activity, immune cells up-regulate telomerase in concert with activation. Nevertheless, during aging and chronic HIV-1 infection, there are high proportions of dysfunctional CD8(+) CTL with short telomeres, suggesting that telomerase is limiting. The present study shows that exposure of CD8(+) T lymphocytes from HIV-infected human donors to a small molecule telomerase activator (TAT2) modestly retards telomere shortening, increases proliferative potential, and, importantly, enhances cytokine/chemokine production and antiviral activity. The enhanced antiviral effects were abrogated in the presence of a potent and specific telomerase inhibitor, suggesting that TAT2 acts primarily through telomerase activation. Our study is the first to use a pharmacological telomerase-based approach to enhance immune function, thus directly addressing the telomere loss immunopathologic facet of chronic viral infection. (+info)
Potential role of ginseng in the treatment of colorectal cancer.
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Colorectal cancer remains one of the most prevalent cancer and a leading cause of cancer related death in the US. Many currently used chemotherapeutic agents are derived from botanicals. Identifying herbal sources, including those from ginseng family, to develop better anti-cancer therapies remains an essential step in advancing the treatment of the cancer. In this article, potential roles of ginseng herbs, especially American ginseng and notoginseng, in colorectal cancer therapeutics are presented. The major pharmacologically active constituents of ginsengs are ginsenosides, which can be mainly classified as protopanaxadiol and protopanaxatriol groups. Structure-activity relationship between their chemical structures and pharmacological activities are discussed. In addition, various steaming temperature and time treatment of the ginseng herbs can change ginsenoside profiles, and enhance their anti-cancer activities. This heat treatment process may increase the role of ginseng in treating colorectal cancer. (+info)
Ginsenoside compound K production from ginseng root extract by a thermostable beta-glycosidase from Sulfolobus solfataricus.
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Ginsenoside compound K was produced from ginseng root extract using a thermostable recombinant beta-glycosidase from Sulfolobus solfataricus. The pH and temperature for maximum production were 5.5 and 90 degrees C. The half-lives of the enzyme were 66, 30, and 1.7 h at 80, 85, and 90 degrees C respectively. The ginsenoside-hydrolyzing activity (Rd>Rb(1)>Rc>Rb(2)) and compound K-producing activity (Rd>Rc>Rb(1)>Rb(2)) of the beta-glycosidase were also determined. At pH 5.5 at 85 degrees C, 1.63 mg/ml of compound K was produced within 12 h by 40 U/ml of enzyme from 1.9 mg/ml of ginsenoside Rb(1), 0.52 mg/ml of ginsenoside Rb(2), 0.92 mg/ml of ginsenoside Rc, and 0.23 mg/ml of ginsenoside Rd in a 10% (w/v) ginseng root extract via two transformation pathways, Rb(1) or Rb(2) --> Rd --> F(2) --> compound K, and Rc --> compound Mc --> compound K. (+info)