Theoretical and Experimental Studies of the Conversion of Chromopyrrolic Acid to an Antitumor Derivative by Cytochrome P450 StaP: The Catalytic Role of Water Molecules

2009 ◽  
Vol 131 (19) ◽  
pp. 6748-6762 ◽  
Author(s):  
Yong Wang ◽  
Hui Chen ◽  
Masatomo Makino ◽  
Yoshitsugu Shiro ◽  
Shingo Nagano ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Experimental Studies ◽  
Water Molecules ◽  
Catalytic Role

scholarly journals Exploring the Metabolism of Loxoprofen in Liver Microsomes: The Role of Cytochrome P450 and UDP-Glucuronosyltransferase in Its Biotransformation

Pharmaceutics ◽  
2018 ◽  
Vol 10 (3) ◽  
pp. 112 ◽  
Author(s):  
Riya Shrestha ◽  
Pil Cho ◽  
Sanjita Paudel ◽  
Aarajana Shrestha ◽  
Mi Kang ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Active Metabolite ◽  
Experimental Studies ◽  
Liver Microsomes ◽  
Cytochrome P450s ◽  
Hydroxylated Metabolites ◽  
Udp Glucuronosyltransferase ◽  
Cyp Isoforms ◽  
Propionic Acid Derivative

Loxoprofen, a propionic acid derivative, non-steroidal anti-inflammatory drug (NSAID) is a prodrug that is reduced to its active metabolite, trans-alcohol form (Trans-OH) by carbonyl reductase enzyme in the liver. Previous studies demonstrated the hydroxylation and glucuronidation of loxoprofen. However, the specific enzymes catalyzing its metabolism have yet to be identified. In the present study, we investigated metabolic enzymes, such as cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT), which are involved in the metabolism of loxoprofen. Eight microsomal metabolites of loxoprofen were identified, including two alcohol metabolites (M1 and M2), two mono-hydroxylated metabolites (M3 and M4), and four glucuronide conjugates (M5, M6, M7, and M8). Based on the results for the formation of metabolites when incubated in dexamethasone-induced microsomes, incubation with ketoconazole, and human recombinant cDNA-expressed cytochrome P450s, we identified CYP3A4 and CYP3A5 as the major CYP isoforms involved in the hydroxylation of loxoprofen (M3 and M4). Moreover, we identified that UGT2B7 is the major UGT isoform catalyzing the glucuronidation of loxoprofen and its alcoholic metabolites. Further experimental studies should be carried out to determine the potency and toxicity of these identified metabolites of loxoprofen, in order to fully understand of mechanism of loxoprofen toxicity.

scholarly journals Role of Active Site Water Molecules and Substrate Hydroxyl Groups in Oxygen Activation by Cytochrome P450 158A2

2005 ◽  
Vol 280 (51) ◽  
pp. 42188-42197 ◽  
Author(s):  
Bin Zhao ◽  
F. Peter Guengerich ◽  
Markus Voehler ◽  
Michael R. Waterman
Keyword(s):  
Cytochrome P450 ◽  
Active Site ◽  
Oxygen Activation ◽  
Water Molecules ◽  
Hydroxyl Groups ◽  
Site Water

scholarly journals The Role of (H2O)1-2 in the CH2O + ClO Gas-Phase Reaction

Molecules ◽  
2018 ◽  
Vol 23 (9) ◽  
pp. 2240 ◽  
Author(s):  
Junyao Li ◽  
Narcisse Tsona ◽  
Lin Du
Keyword(s):  
Rate Constant ◽  
Density Functional ◽  
Hydrogen Transfer ◽  
Kinetic Studies ◽  
Water Molecules ◽  
Phase Reaction ◽  
Functional Theory ◽  
Molecule Reaction ◽  
Catalytic Role

Mechanism and kinetic studies have been carried out to investigate whether one and two water molecules could play a possible catalytic role on the CH2O + ClO reaction. Density functional theory combined with the coupled cluster theory were employed to explore the potential energy surface and the thermodynamics of this radical-molecule reaction. The reaction proceeded through four different paths without water and eleven paths with water, producing H + HCO(O)Cl, Cl + HC(O)OH, HCOO + HCl, and HCO + HOCl. Results indicate that the formation of HCO + HOCl is predominant both in the water-free and water-involved cases. In the absence of water, all the reaction paths proceed through the formation of a transition state, while for some reactions in the presence of water, the products were directly formed via barrierless hydrogen transfer. The rate constant for the formation of HCO + HOCl without water is 2.6 × 10−16 cm3 molecule−1 s−1 at 298.15 K. This rate constant is decreased by 9−12 orders of magnitude in the presence of water. The current calculations hence demonstrate that the CH2O + ClO reaction is impeded by water.

Pharmacogenetics of Clozapine: In Vivo Role of Cytochrome P450 Isoforms and P-Glycoprotein

2008 ◽  
Vol 41 (05) ◽  
Author(s):  
E Jaquenoud-Sirot ◽  
B Knezevic ◽  
G Perla Morena ◽  
P Baumann ◽  
CB Eap
Keyword(s):  
Cytochrome P450 ◽  
P Glycoprotein ◽  
Cytochrome P450 Isoforms

Calculation-and-experimental estimation of the role of the frequency ratio in changing the endurance at two-frequency deformation modes

2019 ◽  
Vol 85 (1(I)) ◽  
pp. 64-71 ◽  
Author(s):  
M. M. Gadenin
Keyword(s):  
High Frequency ◽  
Experimental Studies ◽  
Low Frequency ◽  
Reduction Factor ◽  
Single Frequency ◽  
Cyclic Loads ◽  
Small Ratio ◽  
Harmonic Components ◽  
Deformation Modes

The cycle configuration at two-frequency loading regimes depends on the number of parameters including the absolute values of the frequencies and amplitudes of the low-frequency and high-frequency loads added during this mode, the ratio of their frequencies and amplitudes, as well as the phase shift between these harmonic components, the latter having a significant effect only with a small ratio of frequencies. Presence of such two-frequency regimes or service loading conditions for parts of machines and structures schematized by them can significantly reduce their endurance. Using the results of experimental studies of changes in the endurance of a two-frequency loading of specimens of cyclically stable, cyclically softened and cyclically hardened steels under rigid conditions we have shown that decrease in the endurance under the aforementioned conditions depends on the ratio of frequencies and amplitudes of operation low-frequency low-cycle and high-frequency vibration stresses, and, moreover, the higher the level of the ratios of amplitudes and frequencies of those stacked harmonic processes of loading the greater the effect. It is shown that estimation of such a decrease in the endurance compared to a single frequency loading equal in the total stress (strains) amplitudes can be carried out using an exponential expression coupling those endurances through a parameter (reduction factor) containing the ratio of frequencies and amplitudes of operation cyclic loads and characteristic of the material. The reduction is illustrated by a set of calculation-experimental curves on the corresponding diagrams for each of the considered types of materials and compared with the experimental data.

Helping when desire is low: The role of Expectancy in helping

2020 ◽  
Author(s):  
Małgorzata Kossowska
Keyword(s):  
Experimental Studies ◽  
Helping Behavior ◽  
Perceived Effectiveness ◽  
Do So

One might assume that the desire to help (here described as Want) is the essential driver of helping declarations and/or behaviors. However, even if desire to help is low, helping behavior may still occur if the expectancy regarding the perceived effectiveness of helping is high. We tested these predictions in a set of three experimental studies. In all three, we measured the desire to help (Want) and the Expectancy that the aid would be impactful for the victim; in addition, we manipulated Expectancy in Study 3. In Studies 1 and 3, we measured the participants’ declaration to help while in Study 2, their helping behavior was examined. In all three studies, we used variations of the same story about a victim. The results supported our hypothesis. Thus, the studies help to tease apart the determinants of helping behavior under conditions of lowered desire to do so, an issue of great importance in public policymaking.

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