Induction of CYP2E1 in Liver, Kidney, Brain and Intestine During Chronic Ethanol Administration and Withdrawal: Evidence That CYP2E1 Possesses a Rapid Phase Half-Life of 6 Hours or Less

doi:10.1006/bbrc.1994.2774

Biochemical and Biophysical Research Communications

Volume 205, Issue 2, 15 December 1994, Pages 1064-1071

https://doi.org/10.1006/bbrc.1994.2774 Get rights and content

Abstract

Controversy exists as to whether the induction of CYP2E1 by ethanol occurs via increased protein synthesis or protein stabilization. To address these issues in vivo, we chronically administered ethanol to rats and determined levels of immunoreactive CYP2E1 in liver, kidney, brain and upper gastro-intestinal tract (GI). Our data shows that chronic ethanol administration induces hepatic (5-6-foId over pair-fed controls) and extra-hepatic CYP2E1, an effect which is strikingly absent 12 hours after ethanol withdrawal. No changes in CYP2E1 mRNA were observed at any time, suggesting these changes are mainly post-translational at a blood ethanol concentration of 0.15% w/v. Our experimental data indicates that CYP2E1 possesses a half-life of 6 hours or less in the liver and is rapidly degraded following the removal of ethanol. This pattern of CYP2E1 turnover was also observed in other tissues, suggestive of a similar mode of regulation.

References (0)

Cited by (109)

10-Dehydrogingerdione ameliorates renal endoplasmic reticulum/oxidative stress and apoptosis in alcoholic nephropathy induced in experimental rats
2021, Life Sciences
Chronic alcoholism induces kidney injury (KI), leading to increased mortality in alcoholic hepatitis patients. Endoplasmic reticulum stress (ER) represents the main initiator of kidney diseases and alcoholic nephropathy.
We used alcoholic nephropathy rat model followed by 10-dehydrogingerdione (10-DHGD) intake as potential modulator. This is to focus on ER/oxidative stress/inflammatory and apoptotic pathways involvement.
Alcoholic nephropathy was induced by alcohol administration (3.7 g/kg/body weight) orally and daily for 45 days. 10-DHGD (10 mg/kg/day) was administered either alone or along with alcohol.
Our results demonstrated significant increase in kidney function parameters like f creatinine, urea, uric acid, and blood urea nitrogen (BUN) levels. Renal ER/oxidative stress markers such as cytochrome P450 family two subfamily E member 1 (CYP2E1), C/EBP homologous protein (CHOP), and endoplasmic glucose-regulated protein 78 (GRP-78) demonstrated also significant increase. Inflammatory mediators like nuclear factor-kappa B (NF-kB), tumor necrosis factor-α (TNF-α), and transforming growth factor-β (TGF-β along with apoptotic marker caspase-3 behaved similarly. Antioxidant molecules like reduced glutathione (GSH), superoxide dismutase (SOD), and catalase demonstrated marked decrease.
10-DHGD administration resulted in significant modulation represented by an enhancement in the kidney functions and the histopathological patterns in a conclusion of its potential to ameliorate the pathological changes (kidney injury) induced by alcohol intake.
Cytochrome P450 endoplasmic reticulum-associated degradation (ERAD): therapeutic and pathophysiological implications
2020, Acta Pharmaceutica Sinica B
Citation Excerpt :
Thus, CYP2B1 and CYP2C11, in cultured rat hepatocytes treated with ALD inhibitors [3-methyladenine (3MA)/NH4Cl] or heterologously expressed in a vacuolar (lysosomal) degradation-deficient S. cerevisiae strain, are stabilized relative to those expressed in wild-type (WT) or proteasomal-subunit defective strains17,143,144. CYP2E1 degradation, on the other hand, is biphasic, exhibiting a rapid phase (t1/2, 7 h) and a slow phase (t1/2, 37 h) presumed to reflect its ERAD via UPD and ALD, respectively7,8,14. Upon substrate [isoniazid (INH) or acetone] induction, it largely incurs ALD7,17,139.
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 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.
Lysosome and proteasome dysfunction in alcohol-induced liver injury
2019, Liver Research
The review describes research findings on the influence of alcohol consumption on two crucial catabolic systems in hepatocytes: the lysosome and the ubiquitin-proteasome system (UPS). The lysosome is a membrane-bound organelle that degrades all aging and/or damaged organelles and hydrolyzes all forms of macromolecules. The UPS is mostly proteolytic. It carries out the majority of its functions in the soluble portion of the cytoplasm (cytosol) and degrades nearly all intracellular proteins, particularly those with short half-lives, so that their levels are tightly controlled. Our review will briefly discuss the epidemiology of alcohol abuse and the spectrum of alcohol-induced liver disease (AILD). We will explain why ethanol (EtOH) metabolism, but not EtOH alone, is hepatotoxic. Then, we will summarize how heavy drinking alters hepatic catabolic systems, resulting in liver enlargement that develops from hepatocyte swelling due, in part, to aberrant accumulation of undegraded lipid droplets (steatosis) and undegraded proteins (proteopathy). Our detailed description of each catabolic system will highlight its discoverer(s) and emphasize each system’s characteristics. Most important, we will review the evidence that chronic EtOH consumption disrupts hepatic lysosome biogenesis and inhibits the UPS by impeding hepatic proteasome activity. It will become evident that each of these EtOH-induced defects has far-reaching functional consequences. Finally, we will describe current and potential therapeutic interventions for alleviating EtOH-induced liver injury. The most effective intervention is the cessation of EtOH consumption. However, there are other potential approaches using natural or synthetic compounds that activate autophagy or the proteasome to enhance the degradation of accumulated lipid droplets or proteins, respectively, which could alleviate AILD. These approaches, now in their early stages of investigation, will also be discussed in this review.
Ethanol and hippocampal gene expression: Linking in ethanol metabolism, neurodegeneration, and resistance to oxidative stress
2019, Neuroscience of Alcohol: Mechanisms and Treatment
Our current knowledge on the effects of ethanol in the brain has changed over the past two decades. Although the dramatic and deleterious effects of chronic ethanol consumption on brain structure and physiology has been established, current epidemiological and experimental evidence have revealed that this pleiotropic molecule exhibits biphasic behavior. Indeed, it is now clear that ethanol also triggers beneficial effects when consumed at low to moderate doses. The detrimental and beneficial effects, caused by either chronic or low to moderate exposures to ethanol, respectively, occurring in the hippocampus account for cognitive changes and may lead to either neurodegeneration and memory disruption or neuroprotection, respectively. The plethora of ethanol effects in the hippocampus cannot be satisfactorily explained by direct interactions with specific cellular targets, that is, neurotransmitter receptors, signaling molecules, and ion channels, but rather rely on the modulation of gene expression. In this chapter, we will review the current knowledge on the effects of ethanol exposure on hippocampal gene expression.
Pomegranate prevents binge alcohol-induced gut leakiness and hepatic inflammation by suppressing oxidative and nitrative stress
2018, Redox Biology
Alcoholic liver disease (ALD) is a major chronic liver disease worldwide and can range from simple steatosis, inflammation to fibrosis/cirrhosis possibly through leaky gut and systemic endotoxemia. We investigated whether pomegranate (POM) protects against binge alcohol-induced gut leakiness, endotoxemia, and inflammatory liver damage. After POM pretreatment for 10 days, rats were exposed to 3 oral doses of binge alcohol (5 g/kg/dose) or dextrose (as control) at 12-h intervals. Binge alcohol exposure induced leaky gut with significantly elevated plasma endotoxin and inflammatory fatty liver by increasing the levels of oxidative and nitrative stress marker proteins such as ethanol-inducible CYP2E1, inducible nitric oxide synthase, and nitrated proteins in the small intestine and liver. POM pretreatment significantly reduced the alcohol-induced gut barrier dysfunction, plasma endotoxin and inflammatory liver disease by inhibiting the elevated oxidative and nitrative stress marker proteins. POM pretreatment significantly restored the levels of intestinal tight junction (TJ) proteins such as ZO-1, occludin, claudin-1, and claundin-3 markedly diminished after alcohol-exposure. In addition, the levels of gut adherent junction (AJ) proteins (e.g., β-catenin and E-cadherin) and desmosome plakoglobin along with associated protein α-tubulin were clearly decreased in binge alcohol-exposed rats but restored to basal levels in POM-pretreated rats. Immunoprecipitation followed by immunoblot analyses revealed that intestinal claudin-1 protein was nitrated and ubiquitinated in alcohol-exposed rats, whereas these modifications were significantly blocked by POM pretreatment. These results showed for the first time that POM can prevent alcohol-induced gut leakiness and inflammatory liver injury by suppressing oxidative and nitrative stress.
A physiologically based toxicokinetic model for inhaled ethylene and ethylene oxide in mouse, rat, and human
2018, Toxicology Letters
Ethylene (ET) is the largest volume organic chemical. Mammals metabolize the olefin to ethylene oxide (EO), another important industrial chemical. The epoxide alkylates macromolecules and has mutagenic and carcinogenic properties. In order to estimate the EO burden in mice, rats, and humans resulting from inhalation exposure to gaseous ET or EO, a physiological toxicokinetic model was developed. It consists of the compartments lung, richly perfused tissues, kidneys, muscle, fat, arterial blood, venous blood, and liver containing the sub-compartment endoplasmic reticulum. Modeled ET metabolism is mediated by hepatic cytochrome P450 2E1, EO metabolism by hepatic microsomal epoxide hydrolase or cytosolic glutathione S-transferase in various tissues. EO is also spontaneously hydrolyzed or conjugated with glutathione. The model was validated on experimental data collected in mice, rats, and humans. Modeled were uptake by inhalation, wash-in–wash-out effect in the upper respiratory airways, distribution into tissues and organs, elimination via exhalation and metabolism, and formation of 2-hydroxyethyl adducts with hemoglobin and DNA. Simulated concentration-time courses of ET or EO in inhaled (gas uptake studies) or exhaled air, and of EO in blood during exposures to ET or EO agreed excellently with measured data. Predicted levels of adducts with DNA and hemoglobin, induced by ET or EO, agreed with reported levels. Exposures to 10000 ppm ET were predicted to induce the same adduct levels as EO exposures to 3.95 (mice), 5.67 (rats), or 0.313 ppm (humans). The model is concluded to be applicable for assessing health risks from inhalation exposure to ET or EO.

View all citing articles on Scopus

View full text

Regular ArticleInduction of CYP2E1 in Liver, Kidney, Brain and Intestine During Chronic Ethanol Administration and Withdrawal: Evidence That CYP2E1 Possesses a Rapid Phase Half-Life of 6 Hours or Less

Abstract

Regular Article
Induction of CYP2E1 in Liver, Kidney, Brain and Intestine During Chronic Ethanol Administration and Withdrawal: Evidence That CYP2E1 Possesses a Rapid Phase Half-Life of 6 Hours or Less