Skip to Main content Skip to Navigation
Theses

Les inhibiteurs "suicides" des Cytochromes P450: Etablissement d'une banque de données, mise au point d'un test de screening et étudesstructures-activité concernant des substrats furaniques du CYP 3A4.

Abstract : The inhibition of human cytochrome P450s (CYPs) is one of the most common mechanisms
which can lead to drug-drug interactions. The inhibition of CYPs can be reversible or irreversible.
Irreversible inhibition usually derives from activation of a drug by CYPs into a reactive
metabolite, which tightly binds to the enzyme active site, leading to a long lasting inactivation.
This process is called “suicide inhibition”.
The irreversible inactivation usually implies the formation of a covalent bond between the
metabolite and the enzyme, which can lead to hapten formation and can in some cases trigger an
autoimmune-response.
For these reasons it is of utmost importance to study the mechanism of the CYP inhibition of
new potential drugs as early as possible during the drug discovery process.
In this thesis, a strategy to avoid the development of drugs that might cause CYP suicide
inhibition in patients is proposed.
First, a database with all the chemical entities responsible for suicide inhibition of human and
animal CYPs , was compiled, after a wide literature search. The most common substructures
considered responsible for CYP inactivation are highlighted, and named structural alerts.
Second, a new screening assay, based on fluorescence, to quantitatively assess time dependent
inhibition of CYP3A4 was set and validated. By running this assay, structure-time dependent
inhibition relationships were derived for a group of compounds, differently substituted on the
furan ring, a potentially dangerous substructure.
Third, two compounds containing a furan ring, -a structural alert- and causing time dependent
inhibition on CYP3A4, were used for a series of more specific tests (also using 14C labelled
derivatives). The activity of these two compounds as suicide inhibitors of CYP3A4 was
demonstrated.
Document type :
Theses
Complete list of metadatas

https://tel.archives-ouvertes.fr/tel-00069723
Contributor : Patrick Dansette <>
Submitted on : Friday, May 19, 2006 - 11:39:27 AM
Last modification on : Friday, April 10, 2020 - 5:23:58 PM
Long-term archiving on: : Saturday, April 3, 2010 - 9:33:01 PM

Identifiers

  • HAL Id : tel-00069723, version 1

Citation

Elena Fontana. Les inhibiteurs "suicides" des Cytochromes P450: Etablissement d'une banque de données, mise au point d'un test de screening et étudesstructures-activité concernant des substrats furaniques du CYP 3A4.. Sciences pharmaceutiques. Université René Descartes - Paris V, 2005. Français. ⟨tel-00069723⟩

Share

Metrics

Record views

981

Files downloads

6912