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

Microsomal CYP2E1 metabolizes about 160 hydrophobic exogens, many of which are environmental pollutants. While metabolising xenobiotics CYP2E1 on one hand facilitates in their excretion and on the other hand activates them into the cytotoxins, which may damage the cell. Thus the CYP2E1 activity level significantly affects the processes in cell. Posttranslational stabilization of CYP2E1 seems to be the main mechanism of its regulation in living cell. It is known that degradation of CYP2El takes part in cytoplasmic proteasome system. The efficiency of such degradation depends on the presence of molecular chaperones (HSP90) as was shown from in vitro experiments. But the processes that involve HSP90 in the degradation of CYP2E1 and the mechanisms of transfer of microsomal CYP2E1 to the proteasome system remain unknown. This paper investigates HSP90-dependent processes in mechanisms of CYP2El degradation and the possible role of ethanol in 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.