Differential Time-Dependent Inactivation of P450 3A4 and P450 3A5 by Raloxifene: A Key Role for C239 in Quenching Reactive Intermediates

2007 ◽  
Vol 20 (12) ◽  
pp. 1778-1786 ◽  
Author(s):  
Josh T. Pearson ◽  
Jan L. Wahlstrom ◽  
Leslie J. Dickmann ◽  
Santosh Kumar ◽  
James R. Halpert ◽  
...  
Keyword(s):  
Reactive Intermediates ◽  
Time Dependent ◽  
Dependent Inactivation

Oxypeucedanin is a mechanism-based inactivator of CYP2B6 and CYP2D6

2021 ◽  
Vol 22 ◽  
Author(s):  
Kehan Zhang ◽  
Yilin Li ◽  
Yao Fu ◽  
Tiantian Cui ◽  
Qian Wang ◽  
...  
Keyword(s):  
Pain Relief ◽  
Liver Microsomes ◽  
Reactive Intermediates ◽  
Enzyme Inactivation ◽  
Time Dependent ◽  
Reactive Metabolites ◽  
Angelica Dahurica ◽  
Dependent Inhibition ◽  
Microsomal Incubation

Background: Herbal medicine Angelica dahurica is widely employed for the treatment of rheumatism and pain relief in China. Oxypeucedanin is a major component of the herb. Objectives : The objectives of this study are aimed at the investigation of mechanism-based inactivation of CYP2B6 and CYP2D6 by oxypeucedanin, characterization of the reactive metabolites associated with the enzyme inactivation, and identification of the P450s participating in the bioactivation of oxypeucedanin. Methods : Oxypeucedanin was incubated with liver microsomes or recombinant CYPs2B6 and 2D6 under designed conditions, and the enzyme activities were measured by monitoring the generation of the corresponding products. The resulting reactive intermediates were trapped with GSH and analyzed by LC-MS/MS. Results : Microsomal incubation with oxypeucedanin induced a time-, concentration-, and NADPH-dependent inhibition of CYPs2B6 and 2D6 with kinetic values of KI/kinact 1.82 µM/0.07 min-1 (CYP2B6) and 8.47 µM/0.044 min-1 (CYP2D6), respectively. Ticlopidine and quinidine attenuated the observed time-dependent enzyme inhibitions. An epoxide and/or γ-ketoenal intermediate(s) derived from oxypeucedanin was/were trapped in microsomal incubations. CYP3A4 was the primary enzyme involved in the bioactivation of oxypeucedanin. Conclusion : Oxypeucedanin was a mechanism-based inactivator of CYP2B6 and CYP2D6. An epoxide and/or γ-ketoenal intermediate(s) may be responsible for the inactivation of the two enzymes.

Time-Dependent Inactivation of Aromatase by 6-Alkylandrosta-1,4-diene-3,17-diones. Effects of Length and Configuration of the 6-Alkyl Group†

1996 ◽  
Vol 39 (5) ◽  
pp. 1033-1038 ◽  
Author(s):  
Mitsuteru Numazawa ◽  
Mariko Oshibe ◽  
Satoshi Yamaguchi ◽  
Mii Tachibana
Keyword(s):  
Alkyl Group ◽  
Time Dependent ◽  
Dependent Inactivation

Time-dependent inactivation of steroid C17(20) lyase by 17β-cyclopropyl ether-substituted steroids

1996 ◽  
Vol 6 (1) ◽  
pp. 97-100 ◽  
Author(s):  
Michael R. Angelastro ◽  
Angela L. Marquart ◽  
Philip M. Weintraub ◽  
Cynthia A. Gates ◽  
Marie E. Laughlin ◽  
...  
Keyword(s):  
Time Dependent ◽  
Dependent Inactivation

scholarly journals Rhodopsin kinase: Two mAbs binding near the carboxyl terminus cause time-dependent inactivation

2000 ◽  
Vol 97 (7) ◽  
pp. 3010-3015 ◽  
Author(s):  
C. Bruel ◽  
K. Cha ◽  
L. Niu ◽  
P. J. Reeves ◽  
H. G. Khorana
Keyword(s):  
Time Dependent ◽  
Carboxyl Terminus ◽  
Dependent Inactivation ◽  
Rhodopsin Kinase

EVALUATION OF TIME-DEPENDENT INACTIVATION OF CYP3A IN CRYOPRESERVED HUMAN HEPATOCYTES

2005 ◽  
Vol 33 (6) ◽  
pp. 853-861 ◽  
Author(s):  
Ping Zhao ◽  
Kent L. Kunze ◽  
Caroline A. Lee
Keyword(s):  
Human Hepatocytes ◽  
Time Dependent ◽  
Dependent Inactivation

Glucose-6-phosphatase: is activity regulated by phosphorylation–dephosphorylation?

1983 ◽  
Vol 61 (10) ◽  
pp. 1085-1089 ◽  
Author(s):  
Jasbir Singh ◽  
Richard E. Martin ◽  
Robert C. Nordlie
Keyword(s):  
Protein Kinase ◽  
Protein Phosphorylation ◽  
Alternative Explanation ◽  
Potent Inhibitor ◽  
Liver Microsomes ◽  
Time Dependent ◽  
Rat Liver Microsomes ◽  
Phosphoprotein Phosphatase ◽  
Dependent Inactivation ◽  
Competitive Inhibitors

Incubation of rat liver microsomes with ATP and Mg2+ in the absence or presence of an exogenous protein kinase showed no changes in the activity of glucose-6-phosphatase (D-glucose-6-phosphate phosphohydrolase, EC 3.1.3.9). These observations confirm the recent findings of the Burchells and colleagues and refute on methodological grounds the earlier conclusions of Begley and Craft implicating regulation of this enzyme by protein phosphorylation–dephosphorylation. In other studies, the time-dependent inactivation of microsomal glucose-6-phosphatase by incubation with deoxycholate was used to obtain the inactive enzyme which in the presence of a protein kinase, ATP, and Mg2+ could not be restored to its original level. A number of substrates and competitive inhibitors of glucose-6-phosphatase, most notably vanadate which is the most potent inhibitor of the enzyme identified, stabilized this enzyme against its time-dependent inactivation in the presence of detergent as effectively as did fluoride and molybdate which are also effective competitive inhibitors of glucose-6-phosphatase. An alternative explanation to the involvement of a phosphoprotein phosphatase, as discussed by the Burchells, in the time-dependent inactivation of glucose-6-phosphatase is thus suggested.

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