Cytochrome P450 endoplasmic reticulum-associated degradation (ERAD): Therapeutic and pathophysiological implications

Publication date: Available online 8 November 2019Source: Acta Pharmaceutica Sinica BAuthor(s): Doyoung Kwon, Sung-Mi Kim, Maria Almira CorreiaAbstractThe 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 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...
Source: Acta Pharmaceutica Sinica B - Category: Cancer & Oncology Source Type: research

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ABSTRACT BACKGROUND: Non-alcoholic fatty liver disease is characterized by deposition of lipids in the hepatic parenchyma exceeding 5% of liver weight in the absence of other conditions, such as viral or alcoholic hepatitis and metabolic disease. Non-alcoholic fatty liver disease is the most common form of chronic liver disease in several countries. In addition to liver complications, recent studies have shown a relation between liver fat and sarcopenia. OBJECTIVE: Determine the association between sarcopenia and the severity of non-alcoholic hepatic steatosis diagnosed by abdominal ultrasonography. METHODS: A clinical, cr...
Source: Arquivos de Gastroenterologia - Category: Gastroenterology Source Type: research
Liver diseases, including liver cancer, cirrhosis, and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH), impose a heavy disease burden worldwide [1,2]. Liver cancer and cirrhosis may derive from any chronic liver disease, such as hepatitis B/C virus (HBV/HCV) infections, alcoholic liver disease, NAFLD, haemochromatosis, and autoimmune hepatitis [3]. Over the last four decades, the prevalence of overweight has increased over fourfold in children, and there has been a great relative increase in obesity prevalence with no signs of slowing [4].
Source: Digestive and Liver Disease - Category: Gastroenterology Authors: Tags: Correspondence Source Type: research
This study lists the various anomalies on the basis of 504 references selected from a PubMed search in October 2018. RESULTS: The anomalies are grouped into three categories: anatomical anomalies: duodenal atresia and stenosis (3.9%), duodenal web and annular pancreas; aberrant right subclavian artery (12% of children with DS with cardiac anomaly); Hirschsprung's disease (2.76%); anorectal malformation (1.16%); congenital vascular malformations of the liver; orofacial cleft, bifid uvula (4.63%), and submucous orofacial cleft; esophageal atresia (0.5-0.9%); pyloric stenosis (0.3%); diaphragmatic hernia; malrotation of ...
Source: Archives de Pediatrie - Category: Pediatrics Authors: Tags: Arch Pediatr Source Type: research
AbstractPurpose of ReviewHighly potent anti-retroviral therapy (ART) for the treatment of human immunodeficiency virus (HIV) has led to dramatic improvements in quality of life and lifespan in persons living with HIV (PLWH). PLWH, however, are suffering from other comorbid conditions, including non-alcoholic fatty liver disease (NAFLD). This review summarizes the epidemiology and pathophysiology of NAFLD in PLWH and explores unique diagnostic and treatment considerations in this population.Recent FindingsThough it is well established that there is a high prevalence of NAFLD in PLWH, the mechanisms underlying NAFLD in this ...
Source: Current Hepatitis Reports - Category: Infectious Diseases Source Type: research
Authors: Sun L, Yin H, Liu M, Xu G, Zhou X, Ge P, Yang H, Mao Y Abstract Albumin is the most abundant plasma protein and albumin infusion is commonly used. Conventionally, the biologic and therapeutic effects of albumin have been thought to be due to its oncotic properties. However, albumin has a variety of biologic functions, including molecular transport, anti-oxidation, anti-inflammation, endothelial stabilization, anti-thrombotic effects, and the adjustment of capillary permeability. Despite this, the functions of albumin have not been thoroughly investigated. Recent studies have shown non-alcoholic fatty liver...
Source: Annals of Medicine - Category: Internal Medicine Tags: Ann Med Source Type: research
ra Grieco The biological clock controls at the molecular level several aspects of mammalian physiology, by regulating daily oscillations of crucial biological processes such as nutrient metabolism in the liver. Disruption of the circadian clock circuitry has recently been identified as an independent risk factor for cancer and classified as a potential group 2A carcinogen to humans. Hepatocellular carcinoma (HCC) is the prevailing histological type of primary liver cancer, one of the most important causes of cancer-related death worldwide. HCC onset and progression is related to B and C viral hepatitis, alcoholic an...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Review Source Type: research
This study aimed to evaluate whether the CLD prevalence changed between 1998-2001 and 2016-2017. Data were extracted from the Korea National Health and Nutrition Examination Survey (1998-2001 to 2016-2017; n=25,893). Non-alcoholic fatty liver disease (NAFLD) was defined as a hepatic steatosis index>36 in the absence of any other evidence of CLD. The definition of alcoholrelated liver disease (ALD) was excessive alcohol consumption (≥210 g/week for men and ≥140 g/week for women) and an ALD/NAFLD index>0. The prevalence of NAFLD increased from 18.6% (95% confidence interval [CI], 17.8-19.5%) in 1998-2001 to 21.5%...
Source: Clinical and molecular hepatology - Category: Gastroenterology Tags: Clin Mol Hepatol Source Type: research
AbstractPurpose of ReviewDespite the emergence of non-invasive tests, liver biopsy remains the gold standard for the diagnosis of non-alcoholic fatty liver disease (NAFLD). This review will provide an overview of the histology of adult NAFLD with a focus on current scoring systems, histologic features that predict clinical outcomes, and areas in need of improvement.Recent FindingsStudies during the last two decades have established the histologic features used to categorize NAFLD into non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), described histologic scoring systems that measure disease activit...
Source: Current Hepatitis Reports - Category: Infectious Diseases Source Type: research
Conclusions: The constantly increasing prevalence of NAFLD in the general population can contribute to a growing role of NAFLD/NASH in HCC epidemiology. Moreover, some particular challenges specific for patients with liver steatosis may impede proper HCC diagnosis, treatment and follow-up. PMID: 31631714 [PubMed - as supplied by publisher]
Source: Current Medical Research and Opinion - Category: Research Tags: Curr Med Res Opin Source Type: research
idinis Liver cancer is one of the leading causes of death worldwide due to late diagnosis and scarcity of treatment options. The major risk factor for liver cancer is cirrhosis with the underlying causes of cirrhosis being viral infection (hepatitis B or C), metabolic deregulation (Non-alcoholic fatty liver disease (NAFLD) in the presence of obesity and diabetes), alcohol or cholestatic disorders. Lysophosphatidic acid (LPA) is a bioactive phospholipid with numerous effects, most of them compatible with the hallmarks of cancer (proliferation, migration, invasion, survival, evasion of apoptosis, deregulated metabolism, ...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Review Source Type: research
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