Inhibition of Cytochrome P450 Enzymes

Correia, Maria Almira; Hollenberg, Paul F.

doi:10.1007/978-3-319-12108-6_5

Cited by 84 publications

(76 citation statements)

References 442 publications

(135 reference statements)

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“…2 and Supplementary Table S2). The addition of clotrimazole, a ligand of P450 heme iron [41] , Table S2). Addition of methyl orange (10 mM), a ligand of -cyclodextrin that prevents interaction of the aminoxyl radical with the cyclodextrin [28,42] , did not significantly modify the stability of CD-DEPMPO-OOH and CD-DIPPMPO-OOH in buffer alone or in the presence of RLM ( Fig.…”

Section: Stability Of Superoxide Radical Adducts In the Presence Of Rlmmentioning

confidence: 99%

Metabolic stability of superoxide adducts derived from newly developed cyclic nitrone spin traps

Bézière

Hardy

Poulhès

et al. 2014

Free Radical Biology and Medicine

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Reactive oxygen species (ROS) are by-products of aerobic metabolism involved in the onset and evolution of various pathological conditions. Among them, superoxide radical is of special interest as the origin of several damaging species such as H 2 O 2 , hydroxyl radical, or peroxynitrite (ONOO -). Spin trapping coupled with ESR is a method of choice to characterize these species in chemical and biological systems and the metabolic stability of the spin adducts derived from reaction of superoxide and hydroxyl radicals with nitrones is the main limit to the in vivo application of the method. Recently, new cyclic nitrones bearing a triphenylphosphonium or cyclodextrin moiety have been synthesized and their spin adducts demonstrated increased stability in buffer. In the present manuscript, we studied the stability of the superoxide adducts of four new cyclic nitrones in the presence of liver subcellular fractions and biologically relevant reductants using an original set up combining a stoppedflow device and an ESR spectrometer. The kinetics of disappearance of the spin adducts were analyzed using an appropriate simulation program. Our results highlight the interest of new spin trapping agents CD-DEPMPO and CD-DIPPMPO for specific detection of superoxide with high stability of the superoxide adducts in the presence of liver microsomes.3

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Section: Stability Of Superoxide Radical Adducts In the Presence Of Rlmmentioning

confidence: 99%

Metabolic stability of superoxide adducts derived from newly developed cyclic nitrone spin traps

Bézière

Hardy

Poulhès

et al. 2014

Free Radical Biology and Medicine

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“…Some drugs can additionally covalently modify P450s, resulting in irreversible inhibition, termed mechanism-based inhibition or time-dependent inhibition (TDI) (Silverman, 1995;Correia and de Montellano, 2005;Hollenberg et al, 2008). The in vivo impact of TDI is more difficult to assess than for competitive inhibitors (Grimm et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

“…In this study, we hypothesize that quasi-irreversible TDI results in curved log percent remaining activity versus preincubation time (PRA) plots. Two common functionalities that exhibit metabolite intermediate complex formation are alkylamines and methylenedioxyphenyl groups (Correia and de Montellano, 2005). These groups are metabolized to nitroso and carbene intermediates, respectively, which can coordinate tightly with the heme.…”

Section: Introductionmentioning

confidence: 99%

“…Additional mechanisms such as quasi-irreversible TDI, partial inactivation, or enzyme loss can be modeled with the numerical method. Quasi-irreversible inhibition occurs when enzyme inactivation is slowly reversible (Ma et al, 2000;Correia and de Montellano, 2005;Zhang et al, 2008). Partial inactivation results in an enzyme with reduced activity (Crowley and Hollenberg, 1995;Hollenberg et al, 2008).…”

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confidence: 99%

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A Numerical Method for Analysis of In Vitro Time-Dependent Inhibition Data. Part 1. Theoretical Considerations

Nagar¹,

Jones²,

Korzekwa³

2014

Drug Metab Dispos

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Inhibition of cytochromes P450 by time-dependent inhibitors (TDI) is a major cause of clinical drug-drug interactions. It is often difficult to predict in vivo drug interactions based on in vitro TDI data. In part 1 of these manuscripts, we describe a numerical method that can directly estimate TDI parameters for a number of kinetic schemes. Datasets were simulated for Michaelis-Menten (MM) and several atypical kinetic schemes. Ordinary differential equations were solved directly to parameterize kinetic constants. For MM kinetics, much better estimates of K I can be obtained with the numerical method, and even IC 50 shift data can provide meaningful estimates of TDI kinetic parameters. The standard replot method can be modified to fit non-MM data, but normal experimental error precludes this approach. Non-MM kinetic schemes can be easily incorporated into the numerical method, and the numerical method consistently predicts the correct model at errors of 10% or less. Quasi-irreversible inactivation and partial inactivation can be modeled easily with the numerical method. The utility of the numerical method for the analyses of experimental TDI data is provided in our companion manuscript in this issue of Drug Metabolism and Disposition (Korzekwa et al., 2014b).

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“…One disadvantage of broad substrate specificity is the susceptibility of P450 enzymes to inhibition by covalent inactivation by compounds being metabolized (Correia and Ortiz de Montellano, 2005). This type of inhibition is known as mechanism-based inactivation (MBI) and the loss of enzyme activity can be by covalent adduction of the protein, the heme, or by cross reaction of heme and protein (Hollenberg et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Mechanism-Based Inactivation of Human Cytochrome P450 3A4 by Two Piperazine-Containing Compounds

et al. 2014

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Human cytochrome P450 3A4 (CYP3A4) is responsible for the metabolism of more than half of pharmaceutic drugs, and inactivation of CYP3A4 can lead to adverse drug-drug interactions. The substi-(EMTPP) have been previously identified as mechanism-based inactivators (MBI) of CYP2D6. The present study shows that both SCH 66712 and EMTPP are also MBIs of CYP3A4. Inhibition of CYP3A4 by SCH 66712 and EMTPP was determined to be concentration, time, and NADPH dependent. In addition, inactivation of CYP3A4 by SCH 66712 was shown to be unaffected by the presence of electrophile scavengers. SCH 66712 displays type I binding to CYP3A4 with a spectral binding constant (K s ) of 42.9 6 2.9 mM. The partition ratios for SCH 66712 and EMTPP were 11 and 94, respectively. Whole protein mass spectrum analysis revealed 1:1 binding stoichiometry of SCH 66712 and EMTPP to CYP3A4 and a mass increase consistent with adduction by the inactivators without addition of oxygen. Heme adduction was not apparent. Multiple monooxygenation products with each inactivator were observed; no other products were apparent. These are the first MBIs to be shown to be potent inactivators of both CYP2D6 and CYP3A4.

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Inhibition of Cytochrome P450 Enzymes

Cited by 84 publications

References 442 publications

Metabolic stability of superoxide adducts derived from newly developed cyclic nitrone spin traps

Metabolic stability of superoxide adducts derived from newly developed cyclic nitrone spin traps

A Numerical Method for Analysis of In Vitro Time-Dependent Inhibition Data. Part 1. Theoretical Considerations

Mechanism-Based Inactivation of Human Cytochrome P450 3A4 by Two Piperazine-Containing Compounds

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