Search results for "CYP"
showing 10 items of 480 documents
Studies of the expression of the cytochrome P450IA, P450IIB, and P450IIC gene family in extrahepatic and hepatic tissues.
1990
We have studied the expression of three P-450 gene subfamilies in hepatic and extrahepatic tissues using the sensitive RNAse A protection assay. Members of the P450IA subfamily, which encodes the major methylcholanthrene-inducible cytochromes P-450, were found to be not expressed in extrahepatic tissues of untreated animals, raising the question whether these P-450 play a role in the metabolism of carcinogens in unexposed individuals. In contrast, members of the P450IIB family, some of which encode the major phenobarbital-inducible cytochromes P-450, were found to be expressed in some extrahepatic tissues of untreated rats and here most notably in the lung and in sebaceous glands. Members o…
Kinetics of tienilic acid bioactivation and functional generation of drug–protein adducts in intact rat hepatocytes
2005
13 pages; Drug-induced autoimmune hepatitis is among the most severe hepatic idiosyncratic adverse drug reactions. Considered multifactorial, the disease combines immunological and metabolic aspects, the latter being to date much better known. As for many other model drugs, studies on tienilic acid (TA)-induced hepatitis have evidenced the existence of bioactivation during the hepatic oxidation of the drug, allowing the identification of the neoantigen of anti-LKM2 autoantibodies and the pathway responsible for its formation. However, most of these results are based on the use of microsomal fractions whose relevance to the liver in vivo still needs to be established. In the more complex int…
Transcriptional activation of CYP2C9, CYP1A1, and CYP1A2 by hepatocyte nuclear factor 4alpha requires coactivators peroxisomal proliferator activated…
2006
Hepatocyte nuclear factor 4alpha (HNF4alpha) is a key transcription factor for the constitutive expression of cytochromes P450 (P450s) in the liver. However, human hepatoma HepG2 cells show a high level of HNF4alpha but express only marginal P450 levels. We found that the HNF4alpha-mediated P450 transcription in HepG2 is impaired by the low level of coactivators peroxisomal proliferator activated receptor-gamma coactivator 1alpha (PGC1alpha) and steroid receptor coactivator 1 (SRC1). Reporter assays with a chimeric CYP2C9-LUC construct demonstrated that the sole transfection of coactivators induced luciferase activity in HepG2 cells. In HeLa cells however, CYP2C9-LUC activity only significa…
Modulation of P450 enzymes by Cuban natural products rich in polyphenolic compounds in rat hepatocytes.
2008
This paper reports cytotoxic effects and changes in the P450 system after exposing rat hepatocytes to four polyphenol-rich products widely used in Cuban traditional medicine (Mangifera indica L. (MSBE), Thalassia testudinum (Tt), Erythroxylum minutifolium and confusum extracts). Effects of mangiferin, the main polyphenol in MSBE, were also evaluated. Cytotoxicity was assayed by the MTT test after exposure of cells to the products (50-1000 microg/mL) for 24 or 72 h. The results showed that 500 microg/mL MSBE was moderately cytotoxic after 72 h, while mangiferin was not. Marked reductions in cell viability were produced by Erythroxylum extracts at concentrationsor = 200 microg/mL, whereas onl…
Is metal accumulation in Pomphorhynchus laevis dependent on parasite sex or infrapopulation size?
2010
SUMMARYConcentrations of the elements As, Cd, Co, Cu, Fe, Mn, Mo, Ni, Pb, Sn, V, Zn were analysed by inductively coupled plasma mass spectrometry (ICP-MS) in the acanthocephalan Pomphorhynchus laevis and its fish host Barbus barbus. A total of 27 barbels were collected from the Danube River in autumn 2006 close to the town Kozloduy (685 river kilometer) on the Bulgarian river bank. Fish were divided into 3 groups. According to their P. laevis infrapopulation size hosts were considered as heavily infected (>100 worms per fish) and lightly infected (<20 worms per fish). The third group was used to compare heavy metal concentrations between male and female P. laevis. The 5 elements As, C…
Modelling intestinal absorption of salbutamol sulphate in rats
2005
The objective was to develop a semiphysiological population pharmacokinetic model that describes the complex salbutamol sulphate absorption in rat small intestine. In situ techniques were used to characterize the salbutamol sulphate absorption at different concentrations (range: 0.15-18 mM). Salbutamol sulphate at concentration of 0.29 mM was administered in presence of verapamil (10 and 20 mM), grapefruit juice and sodium azide (NaN3) (0.3, 3 and 6 mM). Different pharmacokinetic models were fitted to the dataset using NONMEM. Parametric and non-parametric bootstrap analyses were employed as internal model evaluation techniques. The validated model suggested instantaneous equilibrium betwee…
In vivo consequences of cholesterol-24S-hydroxylase (CYP46A1) inhibition by voriconazole on cholesterol homeostasis and function in the rat retina
2014
International audience; Cholesterol 24S-hydroxylase (CYP46A1) converts cholesterol into 24S-hydroxycholesterol in neurons and participates in cholesterol homeostasis in the central nervous system, including the retina. We aimed to evaluate the consequences of CYP46A1 inhibition by voriconazole on cholesterol homeostasis and function in the retina. Rats received daily intraperitoneal injections of voriconazole (60 mg/kg), minocycline (22 mg/kg), voriconazole plus minocycline, or vehicle during five consecutive days. The rats were submitted to electroretinography to monitor retinal functionality. Cholesterol and 24S-hydroxycholesterol were measured in plasma, brain and retina by gas chromatog…
Antiulcer activity of Cyperus alternifolius in relation to its UPLC-MS metabolite fingerprint: A mechanistic study
2019
Abstract Background Gastric ulcer is one of the main prevalent gastrointestinal multi-etiological disorders with many associated complications and adverse effects. Our aim was to develop safer antiulcer therapies based on methanol or ethyl acetate extracts of tubers and aerial parts from Cyperus alternifolius. Methods Gastric ulceration was experimentally generated by administration of single oral doses of indomethacin (30 mg/kg) to fasted rats. The animals received methanol or ethyl acetate extracts of C. alternifolius tuber and methanol or ethyl acetate extracts of aerial parts at two dose levels (50 or 100 mg/kg). Ranitidine (50 mg/kg) was used as standard anti-ulcer drug. After 4 h, the…
Molecular mechanisms of hepatotoxic cholestasis by clavulanic acid: Role of NRF2 and FXR pathways.
2021
Treatment of β-lactamase positive bacterial infections with a combination of amoxicillin (AMOX) and clavulanic acid (CLAV) causes idiosyncratic drug-induced liver injury (iDILI) in a relevant number of patients, often with features of intrahepatic cholestasis. This study aims to determine serum bile acid (BA) levels in amoxicillin/clavulanate (A + C)-iDILI patients and to investigate the mechanism of cholestasis by A + C in human in vitro hepatic models. In six A + C-iDILI patients, significant elevations of serum primary conjugated BA definitely demonstrated A + C-induced cholestasis. In cultured human Upcyte hepatocytes and HepG2 cells, CLAV was more cytotoxic than AMOX, and, at subcytoto…
Genetic Polymorphisms and Individualized Tacrolimus Dosing
2010
Background. Genetic polymorphisms of metabolism enzymes or intestinal drug transporters may affect pharmacokinetic responses to immunosuppressive drugs in renal transplant recipients. We sought to identify the frequency of genetic polymorphisms and their importance for individualization of tacrolimus doses. Patients and Methods. We performed an observational study in 35 renal transplant recipients treated with tacrolimus, mycophenolate mofetil, and corticosteroids. Tacrolimus concentrations were determined by immunoanalysis (IMx method; Abbott Diagnostics, Abbott Park, Ill), on 11 blood samples per patient during the first 6 weeks after renal transplantation. For each patient, we calculated…