Search results for "45"
showing 10 items of 1896 documents
Discovery of SI 1/20 and SI 1/22 as Mutual Prodrugs of 5-Fluorouracil and Imidazole-Based Heme Oxygenase 1 Inhibitor with Improved Cytotoxicity in DU…
2023
: In this work, we extend the concept of 5-fluorouracil/heme oxygenase 1 (5-FU/HO-1) inhibitor hybrid as an effective strategy for enhancing 5-FU-based anticancer therapies. For this purpose, we designed and synthesized new mutual prodrugs, named SI 1/20 and SI 1/22, in which the two active parent drugs (i. e., 5-FU and an imidazole-based HO-1 inhibitor) were connected through an easily cleavable succinic linker. Experimental hydrolysis rate, and in silico ADMET predictions were indicative of good drug-likeness and pharmacokinetic properties. Novel hybrids significantly reduced the viability of prostate DU145 cancer cells compared to the parent compounds 5-FU and HO-1 inhibitor administered…
Transcriptional regulation and expression of CYP3A4 in hepatocytes.
2007
CYP3A4 is the most abundantly expressed drug-metabolizing P450 enzyme in human liver and contributes to the metabolism of a large number of drugs in use today. CYP3A4 is constitutively expressed in adult hepatocytes but it can also be transcriptionally induced by a variety of structurally diverse xenochemicals. CYP3A4 strongly contributes to the important variability in the therapeutic and toxic effects of drugs owing to the major role it plays in xenobiotic metabolism and the large intra- and inter-individual variability to which it is subjected. The functional examination of up to 13 kb of the CYP3A4 5'-flanking region has revealed that the regulation of this gene is a complex issue, with…
Regio- and stereoselectivity in the metabolism of benzo[c]phenanthrene mediated by genetically engineered V79 Chinese hamster cells expressing rat an…
1998
Regio- and stereoselective metabolism mediated by cytochrome P450 (CYP) and metabolite-dependent cytotoxicity of benzo[c]phenanthrene (B[c]Ph) and its trans-3,4-dihydrodiol, the metabolic precursor of the carcinogenic fjord-region B[c]Ph-3,4-dihydrodiol 1,2-epoxides (B[c]PhDE), were investigated with V79 Chinese hamster cells genetically engineered for three rat and six human CYP isoforms. The order of the capabilities of the CYP isoforms to metabolize B[c]Ph was as follows: h1A1>r1A1>r1A2>h1B1>h1A2>r2B1>>h2E1>h2A6>h3A4. Regardless of the species, all individual CYP isoforms preferentially catalyzed the oxidation of B[c]Ph at the 5,6-position (K-region) except human CYP1A1 and human CYP1A2,…
Strategies and Molecular Probes to Investigate the Role of Cytochrome P450 in Drug Metabolism
2003
Drug metabolism is the major determinant of drug clearance and, because of polymorphic or inducible expression of drug-metabolising cytochrome P450s (CYPs), is the factor most frequently responsible for interindividual differences in pharmacokinetics. A number of well characterised CYP substrates and inhibitors have been identified that allow precise measurements of individual CYP isoforms. Their use, alone or in combination, facilitates the phenotype characterisation of hepatocytes in vitro and in vivo. Two procedures are used for in vitro investigation of the metabolic profile of a drug: incubation with microsomes and incubation with metabolically competent cells. The major limitation of …
Mangifera indica L. Extract and Mangiferin Modulate Cytochrome P450 and UDP-Glucuronosyltransferase Enzymes in Primary Cultures of Human Hepatocytes
2012
The aqueous stem bark extract of Mangifera indica L. (MSBE) has been reported to have antioxidant, anti-inflammatory and analgesic properties. In previous studies, we showed that MSBE and mangiferin, its main component, lower the activity of some cytochrome P-450 (P450) enzymes in rat hepatocytes and human liver microsomes. In the present study, the effects of MSBE and mangiferin on several P450 enzymes and UDP-glucuronosyltransferases (UGTs) in human-cultured hepatocytes have been examined. After hepatocytes underwent a 48-h treatment with sub-cytotoxic concentrations of the products (50-250 µg/mL), a concentration-dependent decrease of the activity of the five P450 enzymes measured (CYP1A…
Fluorescence-based assays for screening nine cytochrome P450 (P450) activities in intact cells expressing individual human P450 enzymes.
2004
In this study we describe a battery of fluorescence assays for rapid measurement in intact cells of the activity of nine cytochromes P450 (P450s) involved in drug metabolism. The assays are based on the direct incubation of monolayers of cells expressing individual P450 enzymes with a fluorogenic substrate followed by fluorimetric quantification of the product formed and released into incubation medium. For each individual P450 activity, different fluorescence probes were examined, and the one showing the best properties (highest metabolic rates, lowest background fluorescence) was selected: 3-cyano-7-ethoxycoumarin for CYP1A2 and CYP2C19, coumarin for CYP2A6, 7-ethoxy-4-trifluoromethylcoum…
Enzymatic formation of the sarpagan-bridge: a key step in the biosynthesis of sarpagine- and ajmaline-type alkaloids.
1995
The glucoalkaloid strictosidine has been converted under cell-free conditions into 10-deoxysarpagine (= normacusine B) in the presence of a crude soluble enzyme extract and microsomal protein isolated from cell suspensions of Rauwolfia serpentina. The enzymatic formation of this alkaloid bearing the C-5/C-16 bond (sarpagan-bridge), which is characteristic for all sarpagine- and ajmaline-type alkaloids, is dependent on NADPH and oxygen. Inhibition studies indicate that for the synthesis of 10-deoxysarpagine a cytochrome P450 dependent monoxygenase is necessary.
Effect of nutritional imbalances on cytochrome P-450 isozymes in rat liver
1988
Male Sprague-Dawley rats were fed for six weeks either a control diet containing 22% casein (C) and 5% fat (F) or a low-protein diet (6% C, 5% F) or high-lipid diet (30% C, 30% F). A group of rats received a control diet containing 50 ppm of Phenoclor DP6. Three major forms of cytochrome P-450, UT 50, BP 3a and MC 2 were purified from livers of DP6-fed rats and only two forms, UT 50 and PB 3a, were purified from control and dietary groups. The amino acid composition and the catalytic activities towards all substrates tested were only significantly modified in the purified UT 50 P-450 isozyme from rats fed the low-protein diet. The N-terminal sequence analysis shows that cytochrome P-450 UT …
Long-term pulse profile study of the Be/X-ray pulsar SAX J2103.5+4545
2007
Aims. We present the first long-term pulse profile study of the X-ray pulsar SAX J2103.5+4545. Our main goal is to study the pulse shape correlation either with luminosity, time or energy. Methods. This Be/X-ray binary system was observed from 1999 to 2004 by RXTE PCA, and by INTEGRAL from 2002 to 2005, during the Performance and Verification (PV) phase and the Galactic Plane Scan survey (GPS). X-ray pulse profiles were obtained in different energy ranges. The long-term spectral variability of this source is studied. The long-term flux, frequency and spin-up rate histories are computed. A new set of orbital parameters are also determined. Results. The pulse shape is complex and highly varia…
La vida cotidiana de los vecinos de Manila a través de sus testamentos e inventarios de bienes
2019
With the general objective indicated in its title, this work tries to highlight relevant aspects in the continuity of the Spanish domain in the Philippines, dependent on the maintenance of the Spanish capital. The inevitable selection of topics has lead the preferences of this work towards the residents collaboration to defend the city, the conversion of many of them into traders of exotic products and singular slaves owners, and their collaboration to an incredible miscegenation due to the ethnic variety. On the other hand, to follow the footsteps of the first generation of residents in Manila, at the end of the 16th century and during the 17th century, this work gives us some information …