The stereoselective biotransformation of the anti-obesity drug sibutramine in rat liver microsomes and in primary cultures of rat hepatocytes

2005 ◽  
Vol 57 (3) ◽  
pp. 405-410 ◽  
Author(s):  
Marek Link ◽  
Romana Novotná ◽  
Bohumila Suchanová ◽  
Lenka Skálová ◽  
Vladimír Wsól ◽  
...  
Keyword(s):  
Rat Liver ◽  
Primary Cultures ◽  
Liver Microsomes ◽  
Rat Hepatocytes ◽  
Rat Liver Microsomes

Characterization of enzymes responsible for biotransformation of the new antileukotrienic drug quinlukast in rat liver microsomes and in primary cultures of rat hepatocytes

2004 ◽  
Vol 56 (2) ◽  
pp. 205-212 ◽  
Author(s):  
Barbora Szotáková ◽  
Lenka Skálová ◽  
Vendula Baliharová ◽  
Martina Dvorščaková ◽  
Lenka Štorkánová ◽  
...  
Keyword(s):  
Rat Liver ◽  
Primary Cultures ◽  
Liver Microsomes ◽  
Rat Hepatocytes ◽  
Rat Liver Microsomes

scholarly journals Inhibition of phosphatidylcholine synthesis by vasopressin and angiotensin in rat hepatocytes

1982 ◽  
Vol 208 (2) ◽  
pp. 453-457 ◽  
Author(s):  
S Alemany ◽  
I Varela ◽  
J M Mato
Keyword(s):  
Rat Liver ◽  
Liver Microsomes ◽  
Rat Hepatocytes ◽  
Rat Liver Microsomes ◽  
Isolated Rat Hepatocytes ◽  
Fast Transient ◽  
Phosphatidylcholine Synthesis ◽  
Isolated Rat

The addition of 1 microM-vasopressin or -angiotensin to isolated rat hepatocytes induced a fast transient inhibition of the rate of incorporation of [Me-3H]choline into phosphatidylcholine. The cationophore A23187 induced a similar inhibition of phosphatidylcholine synthesis. The addition of micromolar Ca2+ to rat liver microsomes inhibited the activity of CDP-choline: 1,2-diacylglycerol cholinephosphotransferase. This inhibition is due a decrease in the Vmax. of the enzyme without affecting the Km for CDP-choline. It is concluded that Ca2+ regulates phosphatidylcholine synthesis in rat liver.

scholarly journals Evidence that a low-molecular-mass GTP-binding protein is required for store-activated Ca2+ inflow in hepatocytes

1997 ◽  
Vol 328 (2) ◽  
pp. 463-471 ◽  
Author(s):  
C. Kekulu FERNANDO ◽  
B. Roland GREGORY ◽  
Frosa KATSIS ◽  
E. Bruce KEMP ◽  
J. Greg BARRITT
Keyword(s):  
Endoplasmic Reticulum ◽  
Molecular Mass ◽  
G Protein ◽  
Rat Liver ◽  
Liver Microsomes ◽  
Brefeldin A ◽  
Rat Hepatocytes ◽  
Rat Liver Microsomes ◽  
Isolated Rat Hepatocytes ◽  
Gtp Binding

The roles of a monomeric GTP-binding regulatory protein in the activation of store-activated plasma membrane Ca2+ channels and in the release of Ca2+ from the smooth endoplasmic reticulum (SER) in rat liver parenchymal cells were investigated with the use of freshly isolated rat hepatocytes and rat liver microsomes. A low concentration (approx. 130 μM intracellular) of guanosine 5ʹ-[γ-thio]triphosphate (GTP[S]) activated Ca2+ inflow in intact hepatocytes in the absence of an agonist, whereas a high concentration (approx. 530 μM intracellular) of GTP[S] or guanosine 5ʹ-[βγ-imido]triphosphate (p[NH]ppG) inhibited the Ca2+ inflow induced by inhibitors of the activity of the endoplasmic-reticulum Ca2+-ATPase (SERCA) and by vasopressin. GTP (530 μM) prevented the inhibition of Ca2+ inflow by GTP[S] and p[NH]ppG. Brefeldin A and the peptide human Arf-1-(2-17), which inhibit many functions of ADP ribosylation factor (Arf) proteins, inhibited the Ca2+ inflow induced by SERCA inhibitors and vasopressin, and altered the profile of Ca2+ release from the SER. These effects were observed at concentrations of Brefeldin A and Arf-1-(2-17) comparable with those that inhibit the functions of Arf proteins in other systems. Succinylated Arf-1-(2-17) had a negligible effect on Ca2+ inflow. GTP[S] and Arf-1-(2-17) completely inhibited the synergistic action of GTP and Ins(1,4,5)P3 in releasing 45Ca2+ from rat liver microsomes loaded with 45Ca2+. AlF4- (under conditions expected to activate trimeric G-proteins) and succinylated Arf-1-(2-17) had no effect on GTP/Ins(1,4,5)P3-induced 45Ca2+ release, and a mastoparan analogue caused partial inhibition. Arf-1-(2-17) did not inhibit 45Ca2+ release induced by either thapsigargin or ionomycin. It is concluded that a low-molecular-mass G-protein, most probably a member of the Arf protein family, is required for store-activated Ca2+ inflow in rat hepatocytes. The idea that the role of this G-protein is to maintain a region of the SER in the correct intracellular location is discussed briefly.

scholarly journals ACTIVITY OF THE MICROSOMAL OXIDATION SYSTEM IN RAT LIVER UNDER THE INFLUENCE OF SODIUM FLUORIDE

2021 ◽  
pp. 121-124
Author(s):  
I. Yu. Bagmut ◽  
I. L. Kolisnyk
Keyword(s):  
Rat Liver ◽  
Sodium Fluoride ◽  
Liver Microsomes ◽  
Rat Hepatocytes ◽  
The Body ◽  
Endogenous Respiration ◽  
Monooxygenase System ◽  
Rat Liver Microsomes ◽  
Microsomal Oxidation ◽  
Fluoride Intoxication

Summary. The pathogenesis of fluoride intoxication at the molecular, cellular and functional levels has not been sufficiently studied. There are very few modern data on these issues, so they are contradictory, since the effects of this trace element are multifaceted and cannot be characterized unambiguously. The aim of the study – to learn the state of the monooxygenase system of rat hepatocytes under conditions of the formation of fluoride intoxication. Materials and Methods. In the experiment, we used 30 sexually mature rats (N=30) of the Wistar population weighing 200–210 g for 1.5 months. Sodium fluoride solution was administered orally at doses of 1/10 DL50, which was 20 mg/kg of animal body weight. Results. The results of experiments on the study of oxygen consumption by rat liver microsomes under fluoride intoxication indicated that the rate of endogenous respiration of microsomes, the rate of NADPH oxidation, the rate of NADH oxidation in the presence of EDTA, and the rate of lipid peroxidation increase under the influence of fluorides. Sodium fluoride stimulated an increase in all parameters of microsomal oxidation, except for cytochrome b5. It should be assumed that in this case there is an increase in the generation of reactive oxygen species, free radicals, which stimulate the development of free radical processes in the body and are, most likely, the leading link in oxidative stress. Conclusions. These changes indicate a violation of the bioenergetics of hepatocytes associated with the mitochondrial apparatus and the development of hypoxic processes, which lead to a decrease in the activity of redox reactions occurring at the level of intracellular membranes and organelles.

Metabolic Analysis of Triptolide Microspheres in Human, Dog, Rabbit and Rat Liver Microsomes with UPLC-MS/MS Method

2020 ◽  
Vol 17 ◽  
Author(s):  
LiJuan Wang ◽  
Yan Liu ◽  
Rui Li ◽  
DongXian He
Keyword(s):  
Rat Liver ◽  
Liver Microsomes ◽  
Internal Standard ◽  
Gradient Elution ◽  
Rat Liver Microsomes ◽  
Good Precision ◽  
Kinetics Parameters ◽  
Measure Concentration ◽  
Standard Curve ◽  
Variation Of Parameters

Objectives: Triptolide (TPL) has been shown to have a good clinical effect on rheumatoid arthritis (RA). We designed TPL microspheres (TPL-MS) and investigated its metabolic behavior in human, dog, rabbit and rat liver microsomes (HLM, DLM, RLM and SDRLM) with UPLC-MS/MS method. Methods: First, a UPLC-MS/MS method was established to measure concentration of TPL in samples. The sample was separated on a C18 column (2.1×100 mm, 1.8μm) and eluted with a gradient elution. The precursor ion/product ion were m/z 378.1/361.0 for TPL and 260.0/116.2 for the internal standard. Then T1/2, Vmax and CLint were calculated from the above data. Finally, the metabolites of TPL-MS were identified by high-resolution UPLC-MS/MS. The sample was separated on a C18 column (2.1×100 mm, 2.2 μm) and eluted with isocratic elution. Mass spectrometric detection was carried out on a thermo Q-exactive mass spectrometer with HESI. The scanning range of precursor ions was from m/z 50 to m/z 750. Result and Discussion: Through several indicators including standard curve, precision, accuracy, stability, matrix effect and recovery rate, the enzymatic kinetics parameters including T1/2, Vmax and CLint were completed. Several metabolites of TPL-MS were identified. Conclusion: UPLC-MS/MS method is an accurate and sensitive method for determination of TPL in liver microsome samples with good precision, accuracy and stability. The variation of parameters indicated that the microspheres can delay the elimination of TPL in liver microsomes. The metabolism of TPL-MS varied among species, but no new metabolites appeared.

scholarly journals The metabolism of gelsevirine in human, pig, goat and rat liver microsomes

2021 ◽  
Author(s):  
Hua‐Hai Zhang ◽  
Wen‐Jia Yang ◽  
Ya‐Jun Huang ◽  
Wen‐Jing Li ◽  
Shuo‐Xin Zhang ◽  
...  
Keyword(s):  
Rat Liver ◽  
Liver Microsomes ◽  
Rat Liver Microsomes

scholarly journals Detoxification of the tricyclic antidepressant opipramol and its analog – IS-noh by UGT enzymes before and after activation by phase I enzymes in rat liver microsomes

2021 ◽  
Author(s):  
Anna Mieszkowska ◽  
Koleta Hemine ◽  
Anna Skwierawska ◽  
Ewa Augustin ◽  
Zofia Mazerska
Keyword(s):  
Phase I ◽  
Rat Liver ◽  
Phase Ii ◽  
Oxidation Product ◽  
Liver Microsomes ◽  
Correct Selection ◽  
Rat Liver Microsomes ◽  
Recombinant Enzymes ◽  
Data Set ◽  
Phase I Enzymes

AbstractThe present studies were carried out to evaluate the simultaneous one-pot metabolism of opipramol (IS-opi) and analog (IS-noh) by phase I and phase II enzymes present in rat liver microsomes (RLM) as an alternative to separate testing with recombinant enzymes. This approach allows for more time-saving and cost-effective screening of the metabolism of newly discovered drugs. We also considered that the lack of results for phase II, including UGT, often creates problems in correct selection of valuable compounds. Moreover, microsomes data set is richer in the contest and provides medical scientist to determine also the susceptibility of drugs to undergo phase I and then phase II. In the present work, we have shown that IS-noh was metabolized in vitro by phase I enzymes to the oxidation product, which was next transformed with UGTs to glucuronide. The results showed also that the previously known oxidation product of opipramol was changed to previously no reported glucuronidation product by UDP-glucuronosyltransferases. In addition, unlike IS-noh, opipramol did not prove to be the substrate for UGTs. Therefore, tricyclic antidepressants depending on the structure can trigger a different response after contact with UGT enzymes. Some will metabolize directly with UGTs, others only after activation by phase I enzymes.

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