Inhibition of Cytochrome P450 Enzymes

Correia, Maria Almira; Montellano, Paul R. Ortiz de

doi:10.1007/0-387-27447-2_7

Cited by 85 publications

(52 citation statements)

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“…This difference spectrum is characteristic of the formation of a P450 iron-benzodioxole-derived carbene complex [52]. Under the used conditions (0.1 μM CYP2J2, 100 μM 13), the difference spectrum reached its maximal intensity 10 min after the addition of 100μM NADPH.…”

Section: Study Of the Molecular Mechanism Responsible For Cyp2j2 Inacmentioning

confidence: 86%

“…Most of them derive from terfenadone by replacement of its t-butyl group with various R groups of different size and polarity. This includes R groups bearing chemical functions well known to lead to suicide inactivation of cytochrome P450 after in situ oxidation [52][53][54][55][56]. This is the case of the terminal double bond of compound 5, of the CHF 2 function of compound 12, and of the benzo-1,3-dioxole function of compound 13 ( Table 1).…”

Section: Synthesis Of Three Series Of Derivatives Of Terfenadone Dehmentioning

confidence: 99%

“…In that regard, the low IC 50 value observed for compound 14, for which R is a quite polar imidazole group, is a particular case. Its good affinity for CYP2J2 is due to the presence of the imidazole heterocycle, which is a well-known ligand of P450 iron [52] and should strongly bind to the iron of CYP2J2. Accordingly, addition of 14 to a suspension of microsomes from insect cells expressing CYP2J2 led, in difference visible spectroscopy, to a spectrum characterized by a peak at 432 nm and a trough at 415 nm (type II difference spectrum [57]) (data not shown).…”

Section: Comparison Of the Inhibitory Effects Of The Terfenadone And mentioning

confidence: 99%

“…Such P450-dependent oxidations of benzo-1,3-dioxole derivatives are well known to lead to the formation of the corresponding catechol metabolites and to P450 inactivation due to the formation of very stable P450 iron-benzodioxole-derived carbene complexes [52] ( Figure 6). The generally admitted mechanism of these reactions involves the free-radical abstraction of an hydrogen atom of the benzodioxole CH 2 group by the high-valent P450 ironoxo active species.…”

Section: Study Of the Molecular Mechanism Responsible For Cyp2j2 Inacmentioning

confidence: 99%

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Selective, competitive and mechanism-based inhibitors of human cytochrome P450 2J2

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Dijols

Zeldin

et al. 2007

Archives of Biochemistry and Biophysics

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Twenty five derivatives of the drugs terfenadine and ebastine have been designed, synthesized, and evaluated as inhibitors of recombinant human CYP2J2. Compound 14, which has an imidazole substituent, is a good non competitive inhibitor of CYP2J2 (IC 50 = 400 nM). It is not selective towards CYP2J2 as it also efficiently inhibits the other main vascular CYPs, such as CYP2B6, 2C8, 2C9 and 3A4; however, it could be an interesting tool to inhibit all these vascular CYPs. Compounds 4, 5 and 13, which have a propyl, allyl and benzo-1,3-dioxole terminal groups, respectively, are selective CYP2J2 inhibitors. Compound 4 is a high-affinity, competitive inhibitor and alternative substrate of CYP2J2 (K i = 160 ± 50 nM). Compound 5 and 13 are efficient mechanism-based inhibitors of CYP2J2 (k inact /K I values ~3000 L.mol −1 .s −1 ). Inactivation of CYP2J2 by 13 is due to the formation of a stable iron-carbene bond which occurs upon CYP2J2-catalyzed oxidation of 13 with a partition ratio of 18 ± 3. These new selective inhibitors should be interesting tools to study the biological roles of CYP2J2.

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Section: Study Of the Molecular Mechanism Responsible For Cyp2j2 Inacmentioning

confidence: 86%

Section: Synthesis Of Three Series Of Derivatives Of Terfenadone Dehmentioning

confidence: 99%

Section: Comparison Of the Inhibitory Effects Of The Terfenadone And mentioning

confidence: 99%

Section: Study Of the Molecular Mechanism Responsible For Cyp2j2 Inacmentioning

confidence: 99%

See 2 more Smart Citations

Selective, competitive and mechanism-based inhibitors of human cytochrome P450 2J2

Lafite

Dijols

Zeldin

et al. 2007

Archives of Biochemistry and Biophysics

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show abstract

“…One generally accepted approach to ascertaining the contribution of P450 2D6 to a reaction in human liver microsomes is to examine the effect of 1.0 M quinidine on the activity (21,36,37), because at this concentration quinidine is a relatively specific competitive inhibitor of P450 2D6 (36,38) and is not oxidized by the enzyme (39).…”

Section: Inhibition Of Activities By Quinidine In Human Liver Microsomesmentioning

confidence: 99%