Complex Cytochrome P450 kinetics due to multisubstrate binding and sequential metabolism. Part 2. Modeling of experimental data

2021 ◽  
pp. DMD-AR-2021-000554
Author(s):  
Erickson M. Paragas ◽  
Zeyuan Wang ◽  
Ken Korzekwa ◽  
Swati Nagar
Keyword(s):  
Experimental Data ◽  
Cytochrome P450 ◽  
Sequential Metabolism

Cytochrome P450 6M2 from the malaria vector Anopheles gambiae metabolizes pyrethroids: Sequential metabolism of deltamethrin revealed

2011 ◽  
Vol 41 (7) ◽  
pp. 492-502 ◽  
Author(s):  
Bradley J. Stevenson ◽  
Jaclyn Bibby ◽  
Patricia Pignatelli ◽  
Sant Muangnoicharoen ◽  
Paul M. O’Neill ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Anopheles Gambiae ◽  
Malaria Vector ◽  
Sequential Metabolism

No effect of lipoic acid on catalytic activity of cytochrome P450 3A4

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Anna A. Makhova ◽  
Evgeniya V. Shikh ◽  
Tatiana V. Bulko ◽  
Andrei A. Gilep ◽  
Sergei A. Usanov ◽  
...  
Keyword(s):  
Experimental Data ◽  
Cytochrome P450 ◽  
Catalytic Activity ◽  
Lipoic Acid ◽  
Negative Impact ◽  
Chelating Agent ◽  
The Body ◽  
Model Systems ◽  
Cytochrome P450 3A4 ◽  
Complex Therapy

AbstractObjectivesα-Lipoic acid is used as an antioxidant in multivitamin formulations to restore the normal level of intracellular glutathione after depletion caused by environmental pollutants or during physiological aging of the body, as a chelating agent, as a dietary supplement, in anti-aging compositions. Lipoic acid (LA) acts as a buffer in cancer therapy and in therapy of diseases associated with oxidative stress. The effect of LA on the catalytic functions of cytochrome P450 3A4 as the main enzyme of the biotransformation of drugs was studied. It was shown that LA in the concentration range of 50–200 μM affects the stage of electron transfer (stage of cytochrome P450 3A4 heme reduction), decreasing the cathodic reduction current by an average of 20 ± 5%. The kinetic parameters (kcat) of the N-demethylation reaction of erythromycin, the antibiotic of the macrolide group, used as a marker substrate for the comparative analysis of the catalytic activity of cytochrome P450 3A4, both in the presence of α-lipoic acid and in the cytochrome P450 3A4-erythromycin complex, amounted to comparable values of 3.5 ± 0.9 and 3.4 ± 0.9 min−1, respectively. Based on these experimental data, we can conclude that there is no significant effect of α-lipoic acid on the catalysis of cytochrome P450 3A4. These results can be projected on the possibility of using α-lipoic acid in complex therapy without negative impact on the enzymatic cytochrome P450 system.MethodsThe analysis was performed in electrochemical non-invasive model systems for recording the catalytic activity of cytochrome P450 3A4, using screen-printed electrodes, modified with membranous didodecyldimethylammonium bromide.ResultsIt was shown that LA did not affect the N-demethylation of macrolide antibiotic erythromycin. Catalytic constant (kcat) of N-demethylation of erythromycin corresponds to 3.4 ± 0.9 min−1 and in the presence of LA corresponds to 3.5 ± 0.9 min−1.ConclusionsBased on the obtained experimental data, we can conclude that there is no significant effect of α-lipoic acid on individual stages and processes of catalysis of cytochrome P450 3A4. LA can be recommended for inclusion in complex therapy as an antioxidant, antitoxic and chelating compound without negative impact on the enzymatic cytochrome P450 3A4 activity of the human body.

SEQUENTIAL METABOLISM OF 2,3,7-TRICHLORODIBENZO-P-DIOXIN (2,3,7-triCDD) BY CYTOCHROME P450 AND UDP-GLUCURONOSYLTRANSFERASE IN HUMAN LIVER MICROSOMES

2004 ◽  
Vol 32 (8) ◽  
pp. 870-875 ◽  
Author(s):  
Noriyuki Kasai ◽  
Toshiyuki Sakaki ◽  
Raku Shinkyo ◽  
Shin-ichi Ikushiro ◽  
Takashi Iyanagi ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Human Liver ◽  
Liver Microsomes ◽  
Human Liver Microsomes ◽  
Sequential Metabolism ◽  
Udp Glucuronosyltransferase

Sequential Metabolism of Sesamin by Cytochrome P450 and UDP-Glucuronosyltransferase in Human Liver

2011 ◽  
Vol 39 (9) ◽  
pp. 1538-1545 ◽  
Author(s):  
Kaori Yasuda ◽  
Shinichi Ikushiro ◽  
Masaki Kamakura ◽  
Eiji Munetsuna ◽  
Miho Ohta ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Human Liver ◽  
Sequential Metabolism ◽  
Udp Glucuronosyltransferase

Predicting drug–drug interactions by electrochemically driven cytochrome P450 3A4 reactions

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Victoria V. Shumyantseva ◽  
Polina I. Koroleva ◽  
Tatiana V. Bulko ◽  
Gennady V. Sergeev ◽  
Sergei A. Usanov
Keyword(s):  
Experimental Data ◽  
Cytochrome P450 ◽  
Drug Interactions ◽  
Model Systems ◽  
Cytochrome P450 3A4 ◽  
System Method ◽  
Human Cytochrome ◽  
Driven System ◽  
Measuring Tool

Abstract Objectives Human cytochrome P450 3A4 is the most abundant hepatic and intestinal Phase I enzyme that metabolizes approximately 60% marketed drugs. Simultaneous administration of several drugs may result in appearance of drug–drug interaction. Due to the great interest in the combination therapy, the exploration of the role of drug as “perpetrator” or “victim” is important task in pharmacology. In this work the model systems based on electrochemically driven cytochrome P450 3A4 for the analysis of drug combinations was used. We have shown that the analysis of electrochemical parameters of cytochrome P450 3A4 and especially, potential of the start of catalysis, Eonset, possess predictive properties in the determination of the leading (“perpetrator”) properties of drug. Based on these experimental data, we concluded, that the more positive potential of the start of catalysis, Eonset, the more pronounced the role of drug as leading medication. Methods Electrochemically driven cytochrome P450 3A4 was used as probe and measuring tool for the estimation of the role of interacting drugs. Results It is shown that the electrochemical non-invasive model systems for monitoring the catalytic activity of cytochrome P450 3A4 can be used as prognostic devise in assessment of drug/drug interacting medications. Conclusions Cytochrome P450 3A4 activity was studied in electrochemically driven system. Method was implemented to monitor drug/drug interactions. Based on the obtained experimental data, we can conclude that electrochemical parameter such as potential of onset of catalysis, Eonset, has predictive efficiency in assessment of drug/drug interacting medications in the case of the co-administration.

Microdiffraction Patterns of Small Metallic Particles II; Theoretical Analysis

1982 ◽  
Vol 40 ◽  
pp. 668-669
Author(s):  
A. Gómez ◽  
P. Schabes-Retchkiman ◽  
M. José-Yacamán ◽  
T. Ocaña
Keyword(s):  
Experimental Data ◽  
Electron Diffraction ◽  
Theoretical Analysis ◽  
Size Range ◽  
Dynamical Theory ◽  
Metallic Particles ◽  
Splitting Effect

The splitting effect that is observed in microdiffraction pat-terns of small metallic particles in the size range 50-500 Å can be understood using the dynamical theory of electron diffraction for the case of a crystal containing a finite wedge. For the experimental data we refer to part I of this work in these proceedings.

Evidence for ordered Fe3Ni

1987 ◽  
Vol 45 ◽  
pp. 216-217
Author(s):  
K.B. Reuter ◽  
D.B. Williams ◽  
J.I. Goldstein
Keyword(s):  
Experimental Data ◽  
Martensitic Transformation ◽  
Electron Diffraction ◽  
Room Temperature ◽  
Direct Evidence ◽  
Transformation Product ◽  
Iron Meteorites ◽  
X Ray ◽  
Ni Content ◽  
Temperature Transformation

In the Fe-Ni system, although ordered FeNi and ordered Ni3Fe are experimentally well established, direct evidence for ordered Fe3Ni is unconvincing. Little experimental data for Fe3Ni exists because diffusion is sluggish at temperatures below 400°C and because alloys containing less than 29 wt% Ni undergo a martensitic transformation at room temperature. Fe-Ni phases in iron meteorites were examined in this study because iron meteorites have cooled at slow rates of about 10°C/106 years, allowing phase transformations below 400°C to occur. One low temperature transformation product, called clear taenite 2 (CT2), was of particular interest because it contains less than 30 wtZ Ni and is not martensitic. Because CT2 is only a few microns in size, the structure and Ni content were determined through electron diffraction and x-ray microanalysis. A Philips EM400T operated at 120 kV, equipped with a Tracor Northern 2000 multichannel analyzer, was used.

EELS white line intensities calculated for the 3d and 4d metals

1989 ◽  
Vol 47 ◽  
pp. 388-389
Author(s):  
C. C. Ahn ◽  
D. H. Pearson ◽  
P. Rez ◽  
B. Fultz
Keyword(s):  
Experimental Data ◽  
Line Intensity ◽  
Transition Probabilities ◽  
Initial Increase ◽  
White Line ◽  
Hartree Fock ◽  
Line Intensities ◽  
Integrated Intensity ◽  
X Ray Absorption ◽  
The Continuum

Previous experimental measurements of the total white line intensities from L2,3 energy loss spectra of 3d transition metals reported a linear dependence of the white line intensity on 3d occupancy. These results are inconsistent, however, with behavior inferred from relativistic one electron Dirac-Fock calculations, which show an initial increase followed by a decrease of total white line intensity across the 3d series. This inconsistency with experimental data is especially puzzling in light of work by Thole, et al., which successfully calculates x-ray absorption spectra of the lanthanide M4,5 white lines by employing a less rigorous Hartree-Fock calculation with relativistic corrections based on the work of Cowan. When restricted to transitions allowed by dipole selection rules, the calculated spectra of the lanthanide M4,5 white lines show a decreasing intensity as a function of Z that was consistent with the available experimental data.Here we report the results of Dirac-Fock calculations of the L2,3 white lines of the 3d and 4d elements, and compare the results to the experimental work of Pearson et al. In a previous study, similar calculations helped to account for the non-statistical behavior of L3/L2 ratios of the 3d metals. We assumed that all metals had a single 4s electron. Because these calculations provide absolute transition probabilities, to compare the calculated white line intensities to the experimental data, we normalized the calculated intensities to the intensity of the continuum above the L3 edges. The continuum intensity was obtained by Hartree-Slater calculations, and the normalization factor for the white line intensities was the integrated intensity in an energy window of fixed width and position above the L3 edge of each element.

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