The possible mechanisms of CYP2E1 interactions with HSP90 and the influence of ethanol on them

With the help of computational methods we have shown that CYP2E1 can interact with HSP90 resulting in dissociation of CYP2E1 from membrane and formation of the CYP2E1-HSP90 complex for its further transfer to the proteasome for degradation. The twofold increase of both CYP2E1 and HSP90 in the mouse liver under the constant alcohol administration was shown using WB methods. Also, as was shown in silico, ethanol molecule, while binding to the CYP2E1 active site, prevents its interaction with HSP90, thus resulting in accumulation of CYP2E1 in cell.Cytoplasmic HSP90 and membrane-bound CYP2E1 may directly interact with each other as partner proteins, leading to the dissociation of the CYP2E1 from the membrane. This makes it possible to transfer microsomal CYP2E1 in complex with HSP90 to the proteasome for proteolysis. The ethanol molecule inhibits the interaction of HSP90 with CYP2E1 leading to the suppression of its proteasome degradation, thus increasing level of this protein in the cell. Other substrates of CYP2E1 should increase level of this protein in the same way. This may be one of the mechanisms of substrate-dependent regulation of the CYP2E1 expression in the cell.As the main role of microsomal CYP2E1 is detoxification of xenobiotics (exogenous low weight compounds) the highest level of its constitutive expression is found in liver and kidneys, organs that mostly utilize and excrete harmful substances off the organism [1,2]. There are 160 hydrophobic substances of exogenous origin known as substrates for CYP2E1 ( http://cpd.ibmh.msk.su/ webcite). Most of them are environmental pollutants (industrial wastes, fertilizers and solvents), components of food additives, drugs and cosmetics. CYP2E1 on one hand contributes in withdrawal of xenobiotics by metabolizing them in liver (thus taking active part in adaptation of organism to the adverse environmental factors). On the other hand CYP2E1, while metabolizing, may activate its substrates into cytotoxins, which cause