Quercetin prevents type 1 diabetic liver damage through inhibition of CYP2E1

Background
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.

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

A comparison has been made between spatial structures of human CYP2E1 obtained experimentally and those calculated using the computer methods. The structures were characterized by such parameters as total energy, protein pocket volume and total volume of molecules as well as the analysis of spatial geometry. The obtained results have proved that the model calculated and optimized by us can be used for studing the mechanisms of interaction of the active center of the enzyme with substrates and inhibitors. An assumption was made in the course of the research that one of the possible mechanisms of inactivation of the enzyme is the reduction of protein pocket volume, which prevents substrate access to the active center.

Chashchyn Mo

Papers

[Computer modeling of the human cytochrome P-450 2E1 complex formation].