Search results for "Enzyme inducer"
showing 10 items of 47 documents
Human Hepatic Cell Cultures: In Vitro and In Vivo Drug Metabolism
2003
Drug metabolism is the major determinant of drug clearance, and the factor most frequently responsible for inter-individual differences in drug pharmacokinetics. The expression of drug metabolising enzymes shows significant interspecies differences, and variability among human individuals (polymorphic or inducible enzymes) makes the accurate prediction of the metabolism of a new compound in humans difficult. Several key issues need to be addressed at the early stages of drug development to improve drug candidate selection: a) how fast the compound will be metabolised; b) what metabolites will be formed (metabolic profile); c) which enzymes are involved and to what extent; and d) whether dr…
Inducers of heme oxygenase-1.
2008
Heme oxygenase-1 (HO-1) is an inducible rate-limiting enzyme which catalyzes group heme into carbon monoxide, iron and bilirubin. In the recent years, HO-1 expression has been reported as an important protective endogenous mechanism against physical, chemical and biological stress. In this regard, induction of this enzyme has shown beneficial effects in several pathologic conditions, such as inflammatory processes, atherosclerosis, carcinogenesis, ischemia-reperfusion systems or degenerative diseases. Complex intracellular signalling cascades mediate the expression of HO-1 in response to external stimuli, Transcription factors, as nuclear factor E2-related factor-2, activator protein-1, and…
Phosphorylation of cytochromes P450: First discovery of a posttranslational modification of a drug-metabolizing enzyme
2005
Cytochromes P450 (CYP) are important components of xenobiotic-metabolizing monooxygenases (CYP-dependent monooxygenases). Their regulation by induction, most commonly by transcriptional activation, mediated by xenobiotics, normally substrates of the corresponding CYP, is well known and has been widely studied. Our team has discovered an additional important regulation of xenobiotic-metabolizing CYPs pertaining to posttranslational modification by phosphorylation. Individual CYPs are phosphorylated by different protein kinases, leading to CYP isoenzyme-selective changes in the metabolism of individual substrates and consequent drastic changes in the control of genotoxic metabolites. Best stu…
Phosphorylation of carcinogen metabolizing enzymes: regulation of the phosphorylation status of the major phenobarbital inducible cytochromes P-450 i…
1989
We present data showing that the major phenobarbital inducible cytochromes P-450 (cytochrome P-450IIB1 and cytochrome P-450IIB2) were phosphorylated in intact hepatocytes. This phosphorylation was greatly increased by the cAMP derivatives N6-dibutyryl-cAMP and 8-thiomethyl-cAMP mediated by a cAMP-dependent protein kinase. Most importantly the phosphorylation status of cytochromes P-450 was shown to change in the hepatocytes after treatment with glucagon, which is known to increase the level of cAMP in hepatocytes. The observed impact of the hormone glucagon on the phosphorylation of distinct cytochrome P-450 forms in intact hepatocytes reveals the possibility that the enzyme activity of cyt…
Polychlorinated biphenyls, classified as either phenobarbital- or 3-methylcholanthrene-type inducers of cytochrome P-450, are both hepatic tumor prom…
1986
Abstract The cytochrome P -450 isozymes, cytochrome P -450 MC 1 and MC 2 , purified from rats treated with 3-methylcholanthrene (MC), were found by immunohistochemical staining to be strongly induced in the livers of rats treated with 3,3′, 4,4′-tetrachlorobiphenyl (TCBP), while the cytochrome P -450 isozymes, PB 1 and PB 2 , purified from the livers of rats treated with phenobarbital (PB), were shown to be induced in the livers of rats treated with 2,2′, 4,4′, 5,5′-hexachlorobiphenyl (HCBP). The latter compound also strongly induced NADPH-cytochrome P -450-reductase. Following induction, all 5 enzymes were located preferentially in the centrilobular and midzonal region of the liver acinus.…
Ethoxyresorufin-O-deethylase induction potency of polychlorinated diphenyl ethers in H4IIE rat hepatoma cells
1996
Polychlorinated diphenyl ethers (PCDEs) are structurally similar to polychlorinated biphenyls (PCBs), and some PCDE congeners have been reported to cause toxic responses similar to those caused by some of the non-ortho-substituted PCBs, which are mediated by the aryl hydrocarbon receptor (AhR). Twenty-nine PCDEs were tested for their potency as AhR agonists relative to 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) by measuring their ability to induce the cytochrome P-450 1A1-associated enzyme activity, ethoxyresorufin-O-deethylase (EROD), in the H4IIE rat hepatoma cell bioassay. All PCDE congeners tested were found to be inactive as EROD inducers except for PCDE 156, which was a weak E…
Strategies to In Vitro Assessment of Major Human CYP Enzyme Activities by Using Liquid Chromatography Tandem Mass Spectrometry
2008
At the early stage of drug discovery, thousands of new chemical entities (NCEs) may be screened before a single candidate can be identified for development. Determining the role of CYP enzymes in the metabolism of a compound and evaluating the effect of NCEs on human CYP activities are key issues in pharmaceutical development as they may explain inter-subject variability, drug-drug interactions, non-linear pharmacokinetics and toxic effects. Reliable methods for determining enzyme activities are needed to characterize an individual CYP enzyme and to obtain a tool for the evaluation of its role in drug metabolism in humans. Different liquid chromatography tandem mass spectrometry methodologi…
Cryopreserved primary hepatocytes as a constantly available in vitro model for the evaluation of human and animal drug metabolism and enzyme inductio…
2000
The use of primary hepatocytes is now well established for both studies of drug metabolism and enzyme induction. Cryopreservation of primary hepatocytes decreases the need for fresh liver tissue. This is especially important for research with human hepatocytes because availability of human liver tissue is limited. In this review, we summarize our research on optimization and validation of cryopreservation techniques. The critical elements for successful cryopreservation of hepatocytes are (1) the freezing protocol, (2) the concentration of the cryoprotectant [10% dimethyl-sulfoxide (DMSO)], (3) slow addition and removal of DMSO, (4) carbogen equilibration during isolation of hepatocytes and…
Coordinated induction of drug transporters and phase I and II metabolism in human liver slices
2008
Although regulation of phase I drug metabolism in human liver is relatively well studied, the regulation of phase II enzymes and of drug transporters is incompletely characterized. Therefore, we used human liver slices to investigate the PXR, CAR and AhR-mediated induction of drug transporters and phase I and II metabolic enzymes. Precision-cut human liver slices were incubated for 5 or 24 h with prototypical inducers: phenobarbital (PB) (50 mu M) for CAR, beta-naphthoflavone (BNF) (25 mu M) for AhR, and rifampicin (RIF) (10 mu M) for PXR, and gene expression of the phase I enzymes CYP1A1, 1A2, 3A4, 3A5, 2136, 2A6, the phase II enzymes UGT1A1 and 1A6, and the transporters MRP2, MDR1, BSEP, …
Influence of concomitant medications on the total clearance and the risk for supra-therapeutic plasma concentrations of Citalopram. A population-base…
2014
Introduction: The main objective of this study was to investigate the influence of the use of multiple medications and other risk factors on citalopram plasma concentrations. Methods: A retrospective cohort study with a naturalistic population of 957 patients for whom routine therapeutic drug monitoring (TDM) of citalopram had been requested between 2006 and 2013 was conducted. Results: Concomitant drugs inhibiting at least 2 different CYP subtypes involved in the metabolism of citalopram decreased statistically significantly the total clearance (Clt). Compared to younger patients over 64-year-old patients had on average a 4.5 times higher risk rate of supra-therapeutic plasma concentration…