Cytochrome P450 endoplasmic reticulum-associated degradation (ERAD): therapeutic and pathophysiological implications.
10.1016/j.apsb.2019.11.002
- Author:
Doyoung KWON
1
;
Sung-Mi KIM
1
;
Maria Almira CORREIA
1
Author Information
1. Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158-2517, USA.
- Publication Type:Journal Article
- Keywords:
3MA, 3-methyladenine;
AAA, ATPases associated with various cellular activities;
ACC1, acetyl-CoA carboxylase 1;
ACC2, acetyl-CoA carboxylase 2;
ACHE, acetylcholinesterase;
ACOX1, acyl-CoA oxidase 1;
ALD, autophagic-lysosomal degradation;
AMPK1;
AP-1, activator protein 1;
ASK1, apoptosis signal-regulating kinase;
ATF2, activating transcription factor 2;
AdipoR1, gene of adiponectin receptor 1;
Atg14, autophagy-related 14;
CBZ, carbamazepine;
CHIP E3 ubiquitin ligase;
CHIP, carboxy-terminus of Hsc70-interacting protein;
Cytochromes P450;
Endoplasmic reticulum-associated degradation;
FOXO, forkhead box O;
Fas, fatty acid synthase;
GAPDH, glyceraldehyde 3-phosphate dehydrogenase;
INH, isoniazid;
IRS1, insulin receptor substrate 1;
Il-1β, interleukin 1 β;
Il-6, interleukin 6;
Insig1, insulin-induced gene 1;
JNK1;
Lpl, lipoprotein lipase;
Mcp1, chemokine (C–C motif) ligand 1;
Non-alcoholic fatty liver disease;
Non-alcoholic steatohepatitis;
Pgc1, peroxisome proliferator-activated receptor coactivator 1;
SREBP1c, sterol regulatory element binding transcription factor 1c;
Scd1, stearoyl-coenzyme A desaturase;
Tnf, tumor necrosis factor;
UPD, ubiquitin (Ub)-dependent proteasomal degradation;
Ub, ubiquitin;
gp78/AMFR E3 ubiquitin ligase;
gp78/AMFR, autocrine motility factor receptor;
shRNAi, shRNA interference
- From:
Acta Pharmaceutica Sinica B
2020;10(1):42-60
- CountryChina
- Language:English
-
Abstract:
The hepatic endoplasmic reticulum (ER)-anchored cytochromes P450 (P450s) are mixed-function oxidases engaged in the biotransformation of physiologically relevant endobiotics as well as of myriad xenobiotics of therapeutic and environmental relevance. P450 ER-content and hence function is regulated by their coordinated hemoprotein syntheses and proteolytic turnover. Such P450 proteolytic turnover occurs through a process known as ER-associated degradation (ERAD) that involves ubiquitin-dependent proteasomal degradation (UPD) and/or autophagic-lysosomal degradation (ALD). Herein, on the basis of available literature reports and our own recent findings of as well as experimental studies, we discuss the therapeutic and pathophysiological implications of altered P450 ERAD and its plausible clinical relevance. We specifically (i) describe the P450 ERAD-machinery and how it may be repurposed for the generation of antigenic P450 peptides involved in P450 autoantibody pathogenesis in drug-induced acute hypersensitivity reactions and liver injury, or viral hepatitis; (ii) discuss the relevance of accelerated or disrupted P450-ERAD to the pharmacological and/or toxicological effects of clinically relevant P450 drug substrates; and (iii) detail the pathophysiological consequences of disrupted P450 ERAD, contributing to non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) under certain synergistic cellular conditions.
