To fight against aggressions by xenobiotics, the human body has developed three specialized and complementary enzyme systems for the elimination of foreign compounds and which are involved in cellular detoxification (see Figure). These enzymes are cytochromes P450 (CYPs) in the phase functionalization (Phase I metabolism of xenobiotics), conjugation enzymes so-called transferases (phase II) such as the glucuro- or glutathione-S-transferases (including membrane mGST1), and transport proteins such as efflux and P-glycoprotein (P-gp) (Phase III). They are localized in different membranes (endoplasmic reticulum or plasma membrane) and can act synergistically to produce efficient detoxifications of the liver, the principal organ exposed to xenobiotics by the oral route. CYP3A4 and P-gp are characterized by a multispecific molecular recognition towards a great variety of chemical structures and share many common substrates. Because of their hydrophobicity, these common substrates are recognized by these enzymes within the membrane.
We are interested in understanding the functional synergy of the undertaking by mGST1 or P-gp of metabolites produced by P450s, particularly CYP3A4, and in determining the molecular mechanisms of multispecies recognition of these three membrane proteins. These enzymes are thus able to operate "in parallel" to protect the cell against hydrophobic toxic species but also "in series", that is, a product of the enzymatic activity of CYP3A4 could be transported out of the cell by P-gp or via mGST1.
The investigated molecules are in particular drugs in development and compounds found in our environment and that can lead to health problems.