scholarly journals THE ROLE OF CYTOCHROME P450 ISOFORMS OF HEPATOCYTE ENDOPLASMIC RETICULUM IN ETHANOL METABOLISM

2021 ◽  
Vol 5 (2) ◽  
pp. 132-137
Author(s):  
I. P. Sutsko ◽  
◽  
I. N. Semenenya ◽  
A. G. Shlyahtun ◽  
◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cytochrome P450 ◽  
Ethanol Oxidation ◽  
Smooth Endoplasmic Reticulum ◽  
Ethanol Metabolism ◽  
Primary Role ◽  
Liver Alcohol Dehydrogenase ◽  
Cyp Isoforms ◽  
Main Components

Background. Three metabolic pathways that can function simultaneously are known to be involved in ethanol oxidation in the liver: alcohol dehydrogenase pathway, microsomal ethanol-oxidizing system, and catalase pathway. Though the cytochrome P450-dependent microsomal ethanol-oxidizing system plays an insignificant role in metabolism of small amounts of ethanol, it is induced in case of ethanol excess and becomes essential when ethanol is abused. The main components of this system are cytochrome P450 (CYP) isoforms of smooth endoplasmic reticulum. Objective. To characterize the role of the key isoforms of cytochrome P450 in ethanol oxidation. Material and methods. We carried out an analysis of modern literature data on the role of the main isoforms of cytochrome P450 in liver metabolism of ethanol. Results. Data on the primary role of cytochrome CYP2E1 in ethanol metabolism, as well as on the contribution of isoforms CYP1A2, CYP2B1/2, CYP2C, CYP3A4, CYP4B1 to ethanol oxidation are presented. Conclusions. Ethanol is metabolized by many CYPs of endoplasmic reticulum of hepatocytes. The importance of CYP in biotransformation processes in the liver necessitates the study of the role of individual CYP isoforms in ethanol metabolism for predicting changes in the pharmacokinetics of drugs and metabolism of endogenous compounds under the influence of ethanol.

Ethanol Metabolism in Vivo and the Role of Hepatic Microsomal Ethanol Oxidation

1972 ◽  
Vol 33 (3) ◽  
pp. 751-755 ◽  
Author(s):  
Mary K. Roach ◽  
Myrna Khan ◽  
Marguerite Knapp ◽  
W. N. Reese
Keyword(s):  
Ethanol Oxidation ◽  
Ethanol Metabolism

scholarly journals Exploring the Metabolism of Loxoprofen in Liver Microsomes: The Role of Cytochrome P450 and UDP-Glucuronosyltransferase in Its Biotransformation

Pharmaceutics ◽  
2018 ◽  
Vol 10 (3) ◽  
pp. 112 ◽  
Author(s):  
Riya Shrestha ◽  
Pil Cho ◽  
Sanjita Paudel ◽  
Aarajana Shrestha ◽  
Mi Kang ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Active Metabolite ◽  
Experimental Studies ◽  
Liver Microsomes ◽  
Cytochrome P450s ◽  
Hydroxylated Metabolites ◽  
Udp Glucuronosyltransferase ◽  
Cyp Isoforms ◽  
Propionic Acid Derivative

Loxoprofen, a propionic acid derivative, non-steroidal anti-inflammatory drug (NSAID) is a prodrug that is reduced to its active metabolite, trans-alcohol form (Trans-OH) by carbonyl reductase enzyme in the liver. Previous studies demonstrated the hydroxylation and glucuronidation of loxoprofen. However, the specific enzymes catalyzing its metabolism have yet to be identified. In the present study, we investigated metabolic enzymes, such as cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT), which are involved in the metabolism of loxoprofen. Eight microsomal metabolites of loxoprofen were identified, including two alcohol metabolites (M1 and M2), two mono-hydroxylated metabolites (M3 and M4), and four glucuronide conjugates (M5, M6, M7, and M8). Based on the results for the formation of metabolites when incubated in dexamethasone-induced microsomes, incubation with ketoconazole, and human recombinant cDNA-expressed cytochrome P450s, we identified CYP3A4 and CYP3A5 as the major CYP isoforms involved in the hydroxylation of loxoprofen (M3 and M4). Moreover, we identified that UGT2B7 is the major UGT isoform catalyzing the glucuronidation of loxoprofen and its alcoholic metabolites. Further experimental studies should be carried out to determine the potency and toxicity of these identified metabolites of loxoprofen, in order to fully understand of mechanism of loxoprofen toxicity.

scholarly journals Role of p97 and Syntaxin 5 in the Assembly of Transitional Endoplasmic Reticulum

2000 ◽  
Vol 11 (8) ◽  
pp. 2529-2542 ◽  
Author(s):  
Line Roy ◽  
John J.M. Bergeron ◽  
Christine Lavoie ◽  
Rob Hendriks ◽  
Jennifer Gushue ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Secretory Pathway ◽  
Atp Hydrolysis ◽  
Smooth Endoplasmic Reticulum ◽  
Atp Depletion ◽  
Low Density ◽  
Transitional Endoplasmic Reticulum ◽  
Membrane Compartment ◽  
A Cell

Transitional endoplasmic reticulum (tER) consists of confluent rough and smooth endoplasmic reticulum (ER) domains. In a cell-free incubation system, low-density microsomes (1.17 g cc− 1) isolated from rat liver homogenates reconstitute tER by Mg2+GTP- and Mg2+ATP-hydrolysis–dependent membrane fusion. The ATPases associated with different cellular activities protein p97 has been identified as the relevant ATPase. The ATP depletion by hexokinase or treatment with either N-ethylmaleimide or anti-p97 prevented assembly of the smooth ER domain of tER. High-salt washing of low-density microsomes inhibited assembly of the smooth ER domain of tER, whereas the readdition of purified p97 with associated p47 promoted reconstitution. The t-SNARE syntaxin 5 was observed within the smooth ER domain of tER, and antisyntaxin 5 abrogated formation of this same membrane compartment. Thus, p97 and syntaxin 5 regulate assembly of the smooth ER domain of tER and hence one of the earliest membrane differentiated components of the secretory pathway.

scholarly journals Upregulation of Aryl Hydrocarbon Receptor in Granulosa Cells by Endoplasmic Reticulum Stress Contributes to the PCOS Pathophysiology

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A773-A773
Author(s):  
Chisato Kunitomi ◽  
Miyuki Harada ◽  
Jerilee M K Azhary ◽  
Akari Kusamoto
Keyword(s):  
Endoplasmic Reticulum ◽  
Cytochrome P450 ◽  
Er Stress ◽  
Aryl Hydrocarbon Receptor ◽  
Granulosa Cells ◽  
Target Gene ◽  
Downstream Signaling ◽  
Cytochrome P450 1B1 ◽  
Aryl Hydrocarbon

Abstract Studies have demonstrated that endocrine disrupting chemicals (EDC) are involved in the pathophysiology of PCOS, and aryl hydrocarbon receptor (AHR) mediates the cellular effect of EDC by inducing xenobiotic metabolizing enzymes including cytochrome P450 1B1 (CYP1B1). However, recent studies suggest the novel role of AHR in various diseases, including obesity and cancer progression, independent from the EDC metabolism. We previously demonstrated that endoplasmic reticulum (ER) stress, a newly recognized local factor, contributes to PCOS pathology by affecting diverse functions of granulosa cells. We hypothesized that ER stress induces the expression of AHR and activates its downstream signaling in granulosa cells, irrespective of the presence of EDCs, thereby promoting PCOS pathogenesis. At first, we determined the upregulation of AHR, AHR nuclear translocator (ARNT), and AHR target gene cytochrome P450 1B1 (CYP1B1) in the granulosa cells of PCOS patients and model mice by immunohistochemical staining and qPCR. We examined CYP1B1 as a representative AHR target gene. Treatment of cultured human granulosa-lutein cells (GLCs) with tunicamycin (ER stress inducer) upregulated the expression of AHR, ARNT and CYP1B1. Knockdown of AHR decreased the tunicamycin-induced expression and activity of CYP1B1, suggesting the intermediary role of AHR in upregulation of AHR activity by ER stress. To confirm the role of AHR in vivo, we administered the AHR antagonist CH223191 to PCOS model mice. The administration of the antagonist restored estrous cycling and decreased the number of atretic antral follicles, concomitant with downregulation of AHR and CYP1B1 in granulosa cells. Taken together, this study indicates that AHR and downstream signaling are activated by ER stress in GLCs of PCOS. Moreover, downregulation of local AHR expression and activation restores a normal reproductive phenotype in a PCOS mouse model. Our findings demonstrate that AHR activated by ER stress in the follicular microenvironment contributes to PCOS pathology, and that AHR represents a novel therapeutic target for PCOS.

Liver alterations as a result of the 90-day continuous feeding of 2,3,7,8-tetrachlorodibenzo-p-dioxin

1986 ◽  
Vol 44 ◽  
pp. 364-365
Author(s):  
J.N. Turner ◽  
D.N. Collins
Keyword(s):  
Endoplasmic Reticulum ◽  
Smooth Endoplasmic Reticulum ◽  
Complex Mixture ◽  
Environmental Toxins ◽  
Bile Canaliculi ◽  
Cytoplasmic Vacuoles ◽  
Continuous Feeding ◽  
Tetrachlorodibenzo P Dioxin ◽  
Dose Levels

Chlorinated hydrocarbons are a highly toxic, ubiquitous class of environmental toxins of which 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) is the most toxic. PCB pyrolysates contain a complex mixture of these chemicals and have been shown to produce extensive alterations in the liver of guinea pig hepatocytes, including proliferated smooth endoplasmic reticulum (SER), concentric membrane arrays (CMA) which are a condensation of proliferated SER, and cytoplasmic vacuoles. A mechanism of membrane excretion into the bile canaliculi and sinusoids has been proposed to account for these alterations and their relationship to each other. This report demonstrates the proposed mechanism for a purified compound (TCDD) fed continuously for 90 days and further elucidates the role of the cytoplasmic vacuoles which are observed for dose levels at which no other alteration is present.

scholarly journals Role of superoxide anion radicals in ethanol metabolism by blood monocyte-derived human macrophages.

1989 ◽  
Vol 169 (3) ◽  
pp. 755-763 ◽  
Author(s):  
S N Wickramasinghe
Keyword(s):  
Superoxide Anion ◽  
Ethanol Oxidation ◽  
Fold Increase ◽  
Ethanol Metabolism ◽  
Blood Monocyte ◽  
Human Macrophages ◽  
20 Nm ◽  
Superoxide Anion Radicals ◽  
Anion Radicals

The effects of a number of additives on the rate of conversion of ethanol (1 mg/ml; 21.7 mM) to acetate by monolayers of blood monocyte-derived human macrophages were investigated. The additives studied were superoxide dismutase (SOD; 1,500 U/ml), catalase (1,500 U/ml), tetrahydrofurane (20 mM), and PMA (20 nM), either singly or in various combinations. SOD, catalase, SOD plus catalase, tetrahydrofurane, and tetrahydrofurane plus SOD inhibited ethanol oxidation by 49.2, 12.1, 52.9, 60.4, and 66.8%, respectively. PMA caused a 4.0-8.3-fold increase in the rate of ethanol metabolism and this increase was completely suppressed in the presence of SOD. The data indicate that a substantial proportion of the ethanol metabolism by both unstimulated and PMA-stimulated blood monocyte-derived macrophages was dependent on the generation of superoxide anion radicals.

scholarly journals Retention of membrane proteins by the endoplasmic reticulum.

1985 ◽  
Vol 101 (5) ◽  
pp. 1724-1732 ◽  
Author(s):  
R Brands ◽  
M D Snider ◽  
Y Hino ◽  
S S Park ◽  
H V Gelboin ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Monoclonal Antibody ◽  
Endoplasmic Reticulum ◽  
Cytochrome P450 ◽  
Membrane Proteins ◽  
Nuclear Envelope ◽  
Smooth Endoplasmic Reticulum ◽  
Membrane Glycoprotein ◽  
Glucosidase Ii ◽  
Er Membrane

We have used a monoclonal antibody specific for a hydrocarbon-induced cytochrome P450 to localize, by electron microscopy, the epitope-specific cytochrome P450. The cytochrome was found in the rough and smooth endoplasmic reticulum (ER) and the nuclear envelope of hepatocytes. Significant quantities of cytochrome P450 were not found in Golgi stacks. We also could not find any evidence of Golgi-associated processing of the Asn-linked oligosaccharide chains of two well-characterized ER membrane glycoprotein enzymes (glucosidase II and hexose-6-phosphate dehydrogenase), or of the oligosaccharides attached to the bulk of the glycoproteins of the ER membrane. We conclude that these ER membrane proteins are efficiently retained during a process of highly selective export from this organelle.

The submicrosomal distribution of dolichol and dolichol phosphokinase activity in rat liver

1982 ◽  
Vol 60 (1) ◽  
pp. 36-41 ◽  
Author(s):  
Jack W. Rip ◽  
Kenneth K. Carroll
Keyword(s):  
High Pressure ◽  
Endoplasmic Reticulum ◽  
Rat Liver ◽  
Smooth Endoplasmic Reticulum ◽  
Glycoprotein Synthesis ◽  
Dolichyl Phosphate ◽  
Glycoprotein Processing ◽  
Specific Activities ◽  
High Concentrations

Microsomes were isolated from rat liver and fractionated into Golgi, smooth endoplasmic reticulum (SER), and rough endoplasmic reticulum (RER) components, and the purity of these fractions was determined. The dolichol content of each of the three fractions was estimated, using high-pressure liquid chromatography. Although highest concentrations (1940 ng/mg protein) were found in Golgi, the RER contained the largest absolute amounts. The presence of large quantities of dolichol in RER is consistent with the role of dolichol as an intermediate in asparagine-linked glycoprotein synthesis. RER and SER fractions contained high specific activities for dolichol phosphokinase, while the activity in Golgi was quite low. High concentrations of dolichol in Golgi and high dolichol phosphokinase activity in SER suggest that dolichol (and dolichyl phosphate) may be utilized in Golgi for glycoprotein processing and in the transmembrane movement of sugars such as galactose.

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