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Doyoung Kwon, Sung-Mi Kim, Maria Almira Correia. Cytochrome P450 endoplasmic reticulum-associated degradation (ERAD): therapeutic and pathophysiological implications[J]. Acta Pharmaceutica Sinica B, 2020, 10(1): 42-60

Cytochrome P450 endoplasmic reticulum-associated degradation (ERAD): therapeutic and pathophysiological implications
Doyoung Kwona, Sung-Mi Kima, Maria Almira Correiaa,b,c,d
a Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158-2517, USA;
b Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158-2517, USA;
c Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158-2517, USA;
d The Liver Center, University of California San Francisco, San Francisco, CA 94158-2517, USA
Abstract:
The hepatic endoplasmic reticulum (ER)-anchored cytochromes P450 (P450s) are mixedfunction 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 ubiquitindependent proteasomal degradation (UPD) and/or autophagic-lysosomal degradation (ALD). Herein, on the basis of available literature reports and our own recent findings of in vitro as well as in vivo 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.
Key words:    Cytochromes P450    Endoplasmic reticulumassociated degradation    CHIP E3 ubiquitin ligase    gp78/AMFR E3 ubiquitin ligase    JNK1    AMPK1    Non-alcoholic fatty liver disease    Non-alcoholic steatohepatitis   
Received: 2019-07-09     Revised: 2019-10-30
DOI: 10.1016/j.apsb.2019.11.002
Funds: We thank Mr. Chris Her for liver cell isolation at the UCSF Liver Center Core on Cell & Tissue Biology, supported by NIDDK Center Grant DK26743. This work was supported by NIH Grants GM44037 and DK26506 (USA) to Maria Almira Correia.
Corresponding author: Maria Almira Correia     Email:almira.correia@ucsf.edu
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Doyoung Kwon
Sung-Mi Kim
Maria Almira Correia

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