Regular ArticleCharacterization of Cytochrome P4502E1 Turnover in Transfected HepG2 Cells Expressing Human CYP2E1
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Enzyme Regulation
2018, Comprehensive Toxicology: Third EditionCytochrome P450 and Oxidative Stress in the Liver
2017, Liver Pathophysiology: Therapies and AntioxidantsHuman liver cytochrome P450 3A4 ubiquitination: Molecularrecognition by UBC7-gp78 autocrine motility factor receptor and UbcH5a-CHIP-Hsc70-Hsp40 E2-E3 ubiquitin ligase complexes
2015, Journal of Biological ChemistryCitation Excerpt :Both of these features are consistent with their UPS-mediated turnover being qualified as an ER-associated degradation (ERAD) (17–19), specifically an “ERAD-C” process (20–22) with CYPs 3A and 2E1 as its typical physiological substrates. This is equally true of the ethanol-inducible CYP2E1 (23–30), a liver P450 noted for its pathogenic role in alcoholic liver disease, diabetes, obesity, and oxidative stress (31–33). We and others have documented that in this ERAD-C process, CYPs 3A and CYP2E1 are first phosphorylated by protein kinases (PKA and PKC) (30, 34–38), ubiquitinated by the cytosolic UbcH5a-CHIP-Hsc70-Hsp40 and UBC7-dependent ER-integral polytopic gp78 E2-E3-Ub-ligase complexes (29, 30, 37–40), extracted from the ER membrane by the Npl4-Ufd1-p97/VCP-AAA ATPase chaperone complex (12, 41), and then delivered to the 26 S proteasome for degradation.
Inhibition of CYP2E1 leads to decreased advanced glycated end product formation in high glucose treated ADH and CYP2E1 over-expressing VL-17A cells
2013, Biochimica et Biophysica Acta - General SubjectsCitation Excerpt :Further diallyl sulfide proved to be the most effective inhibitor for hyperglycemia induced lipid peroxidation with methyl pyrazole exerting lesser inhibitory effect and pyrazole causing a small increase in the lipid peroxidation. The increase in lipid peroxidation with pyrazole in 50 mM glucose treated VL-17A cells can also be corroborated with pyrazole acting as an inducer for CYP2E1 [37–40] assuming a greater role than its ability to inhibit ADH in some instances. While diallyl sulfide caused a maximal decrease in HNE adduct formation in high glucose treated VL-17A cells as evident from greatly decreased staining, 4-methyl pyrazole inhibited HNE adduct formation to a lesser extent and pyrazole caused the least inhibition of HNE adduct formation stressing upon the role of CYP2E1 mediated ROS in lipoperoxidative protein damage under hyperglycemic condition in liver cells.
Ubiquitin-dependent proteasomal degradation of human liver cytochrome P450 2E1: Identification of sites targeted for phosphorylation and ubiquitination
2011, Journal of Biological ChemistryCitation Excerpt :Although the precise nature of these CYP2E1 determinants remains to be fully elucidated, it is tempting to speculate that they may include “phosphodegrons” (see below). In cultured human hepatocytes, this CYP2E1 ERAD/UPS process is not only inhibited by the proteasomal inhibitors but is also enhanced upon DDEP-mediated mechanism-based CYP2E1 inactivation (Fig. 4), consistent with previous reports employing other CYP2E1 suicide inactivators (18–22). Thus, structural inactivation of the enzyme apparently damages the protein, resulting in the exposure of additional degrons or targeting of additional residues for post-translational modification that marks the protein for ERAD/UPS.
Enzyme Regulation
2010, Comprehensive Toxicology, Second Edition
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