Search results for "cytochrome p450"
showing 10 items of 135 documents
Effect of genetic variation in CYP450 on Gonadal impairment in a European cohort of female childhood cancer survivors, based on a candidate gene appr…
2021
Background: Female childhood cancer survivors (CCSs) carry a risk of therapy-related gonadal dysfunction. Alkylating agents (AA) are well-established risk factors, yet inter-individual variability in ovarian function is observed. Polymorphisms in CYP450 enzymes may explain this variability in AA-induced ovarian damage. We aimed to evaluate associations between previously identified genetic polymorphisms in CYP450 enzymes and AA-related ovarian function among adult CCSs. Methods: Anti-Müllerian hormone (AMH) levels served as a proxy for ovarian function in a discovery cohort of adult female CCSs, from the pan-European PanCareLIFE cohort (n = 743
The capacity of liver microsomes to form benzo[a]pyrene-diolepoxide-DNA adducts and induction of cytochrome P450 1A in feral fish exposed to pulp mil…
1996
An investigation was made of cytochrome P4501A (CYP1A) induction, determined by the activity of EROD (7-ethoxyresorufin O-deethylase), and formation of benzo[a]pyrene-diolepoxide-DNA (BPDE-DNA) adducts, measured by synchronous fluorescence spectrophotometry, in liver microsomes of perch (Perca fluviatilis), bream (Abramis brama), and roach (Rutilus rutilus). Fish were collected from the southern part of Lake Saimaa (Finland), an area polluted by effluents from the pulp and paper industry. In addition, two conjugation enzymes (UDP-glucuronosyltransferase and glutathione S-transferase) were determined. Overall, when compared to an upstream reference, EROD activity was higher in fish at waters…
Cytochrome P450 reaction phenotyping and inhibition and induction studies of pinostrobin in human liver microsomes and hepatocytes
2017
Pinostrobin (PI, 5-hydroxy-7-methoxyflavanone) is a natural flavonoid known for its rich pharmacological activities. The objective of this study was to identify the human liver cytochrome P450 (CYP450) isoenzymes involved in the metabolism of PI. A single hydoxylated metabolite was obtained from PI after an incubation with pooled human liver microsomes (HLMs). The relative contributions of different CYP450s were evaluated using CYP450-selective inhibitors in HLMs and recombinant human CYP450 enzymes, and the results revealed the major involvement of CYP1A2, CYP2C9 and CYP2E1 in PI metabolism. We also evaluated the ability of PI to inhibit and induce human cytochrome P450 enzymes in vitro. H…
An update on metabolism studies using human hepatocytes in primary culture
2008
Background: Cultured human hepatocytes are the closest in vitro model to human liver and constitute a very predictive model for drug metabolism in vivo. The variability observed in human hepatocytes reflects the existing phenotypic heterogeneity of cytochrome P450 expression in human liver. Objectives: As drug metabolism is the major source of pharmacokinetic variability in human beings, the main areas of current drug metabolism research in human hepatocytes are reviewed. Methods: To speed up the selection of drug candidates, the evaluation of metabolic stability, metabolite profiling and identification, and drug–drug interaction potential are key issues in drug development. Results/conclus…
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 …