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1.
Article in Chinese | WPRIM | ID: wpr-887869

ABSTRACT

Objective To explore the function and mechanism of related genes in the occurrence and development of liver cancer, and the possibility of key genes as potential biomarkers and prognostic indicators for the treatment of liver cancer.Methods We selected 4 datasets(GSE57957, GSE121248, GSE36376 and GSE14520)from the GEO database.With


Subject(s)
Biomarkers, Tumor/genetics , Carrier Proteins , Computational Biology , Cytochrome P-450 CYP2E1 , Cytochrome P-450 CYP3A , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Gene Regulatory Networks , Glycoproteins , Humans , Liver Neoplasms/genetics , Prognosis , Protein Interaction Maps
2.
Braz. j. infect. dis ; 23(6): 381-387, Nov.-Dec. 2019. tab, graf
Article in English | LILACS | ID: biblio-1089317

ABSTRACT

ABSTRACT Setting: Treatment of tuberculosis (TB) can result in Drug-Induced Liver Injury (DILI) since hepatotoxic metabolites are formed during the biotransformation of isoniazid (INH).DILI can be related to the genetic profile of the patient. Single nucleotide polymorphisms in the CYP2E1 gene and GSTM1 and GSTT1 deletion polymorphisms have been associated with adverse events caused by INH. Objective: To characterize the genetic polymorphisms of CYP2E1, GSTT1 and GSTM1 in TB carriers. Design: This is an observational prospective cohort study of 45 patients undergoing treatment of TB. PCR-RFLP and multiplex-PCR were used. Results: The distribution of genotypic frequency in the promoter region (CYP2E1 gene) was: 98% wild genotype and 2% heterozygous. Intronic region: 78% wild genotype; 20% heterozygous and 2% homozygous variant. GST enzyme genes: 24% Null GSTM1 and 22% Null GSTT1. Patients with any variant allele of the CYP2E1 gene were grouped in the statistical analyses. Conclusion: Patients with the CYP2E1 variant genotype or Null GSTT1 showed higher risk of presenting DILI (p = 0.09; OR: 4.57; 95% CI: 0.75-27.6). Individuals with both genotypes had no increased risk compared to individuals with one genotype.


Subject(s)
Humans , Male , Female , Adolescent , Adult , Middle Aged , Aged , Aged, 80 and over , Young Adult , Tuberculosis, Pulmonary/drug therapy , Genetic Predisposition to Disease/genetics , Chemical and Drug Induced Liver Injury/genetics , Antitubercular Agents/adverse effects , Polymorphism, Genetic , Tuberculosis, Pulmonary/enzymology , Prospective Studies , Cytochrome P-450 CYP2E1 , Cytochrome P-450 Enzyme System/genetics , Chemical and Drug Induced Liver Injury/enzymology , Cytochrome P450 Family 2 , Genotype , Liver/drug effects , Liver/enzymology , Antitubercular Agents/therapeutic use
3.
Frontiers of Medicine ; (4): 104-111, 2019.
Article in English | WPRIM | ID: wpr-772708

ABSTRACT

Mitochondrion-localized retinol dehydrogenase 13 (Rdh13) is a short-chain dehydrogenase/reductase involved in vitamin A metabolism in both humans and mice. We previously generated Rdh13 knockout mice and showed that Rdh13 deficiency causes severe acute retinal light damage. In this study, considering that Rdh13 is highly expressed in mouse liver, we further evaluated the potential effect of Rdh13 on liver injury induced by carbon tetrachloride (CCl). Although Rdh13 deficiency showed no significant effect on liver histology and physiological functions under regular culture, the Rdh13 mice displayed an attenuated response to CCl-induced liver injury. Their livers also exhibited less histological changes and contained lower levels of liver-related metabolism enzymes compared with the livers of wild-type (WT) mice. Furthermore, the Rdh13 mice had Rdh13 deficiency and thus their liver cells were protected from apoptosis, and the quantity of their proliferative cells became lower than that in WTafter CCl exposure. The ablation of Rdh13 gene decreased the expression levels of thyroid hormone-inducible nuclear protein 14 (Spot14) and cytochrome P450 (Cyp2e1) in the liver, especially after CCl treatment for 48 h. These data suggested that the alleviated liver damage induced by CCl in Rdh13 mice was caused by Cyp2e1 enzymes, which promoted reductive CCl metabolism by altering the status of thyroxine metabolism. This result further implicated Rdh13 as a potential drug target in preventing chemically induced liver injury.


Subject(s)
Alcohol Oxidoreductases , Genetics , Animals , Carbon Tetrachloride Poisoning , Chemical and Drug Induced Liver Injury , Pathology , Cytochrome P-450 CYP2E1 , Metabolism , Female , Immunohistochemistry , Liver , Pathology , Male , Mice , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Knockout , Nuclear Proteins , Metabolism , Transcription Factors , Metabolism
4.
Laboratory Animal Research ; : 107-113, 2019.
Article in English | WPRIM | ID: wpr-786397

ABSTRACT

Acetaminophen (APAP) is the most common antipyretic analgesic worldwide. However, APAP overdose causes severe liver injury, especially centrilobular necrosis, in humans and experimental animals. At therapeutic dosage, APAP is mainly metabolized by sulfation and glucuronidation, and partly by cytochrome P450–mediated oxidation. However, APAP overdose results in production of excess reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI), by cytochromes P450; NAPQI overwhelms the level of glutathione (GSH), which could otherwise detoxify it. NAPQI binds covalently to proteins, leading to cell death. A number of studies aimed at the prevention and treatment of APAP-induced toxicity are underway. Rats are more resistant than mice to APAP hepatotoxicity, and thus mouse models are mainly used. In the present study, we compared the toxic responses induced by APAP overdose in the liver of ICR mice obtained from three different sources and evaluated the usability of the Korl:ICR stock established by the National Institute of Food and Drug Safety Evaluation in Korea. Administration of APAP (300 mg/kg) by intraperitoneal injection into male ICR mice enhanced CYP2E1 protein expression and depleted hepatic GSH level 2 h after treatment accompanied with significantly increased level of hepatic malondialdehyde, a product of lipid peroxidation. Regardless of the source of the mice, hepatotoxicity, as evidenced by activity of serum alanine aminotransferase, increased from 8 h and peaked at 24 h after APAP treatment. In summary, hepatotoxicity was induced after the onset of oxidative stress by overdose of APAP, and the response was the same over time among mice of different origins.


Subject(s)
Acetaminophen , Alanine Transaminase , Animals , Cell Death , Cytochrome P-450 CYP2E1 , Cytochromes , Glutathione , Humans , Injections, Intraperitoneal , Korea , Lipid Peroxidation , Liver , Male , Malondialdehyde , Mice , Mice, Inbred ICR , Necrosis , Oxidative Stress , Rats
5.
Cad. Saúde Pública (Online) ; 35(7): e00198618, 2019. tab
Article in English | LILACS | ID: biblio-1011709

ABSTRACT

Benzene is one of the most important substances for assessment, due to its significant use, the environmental contamination resulting from its emission and the effects on human health. It is classified by the International Agency for Research on Cancer (IARC) as a known carcinogen to humans (group 1) and associated with the development of leukemia. In general, the population is exposed to this substance by inhaling contaminated air, which varies according to the location and intensity of its potential sources. The petrochemical industry is one of the most important sources of this compound. The municipality of Duque de Caxias, specifically the Campos Elíseos district, in Rio de Janeiro State, Brazil, houses the Industrial Complex of Campos Elíseos (PICE), a grouping of over 25 industries, which includes the second largest oil refinery in Brazil. Environmental contamination from the PICE has been recognized, but there is a lack of studies concerning its impact on the health of the surrounding population. S-phenylmercapturic acid (S-PMA) concentrations ranging from 0.80 to 8.01μg.g-1 creatinine were observed in the local population, apparently related to hematological changes also observed in exposed population. The quantifiable presence of urinary S-PMA from the benzene metabolism is associated with the fact that 60% of the participants present specific hematological changes, which may be due to the environmental benzene exposure. The allele and genotype frequencies of the CYP2E1 and NQO1 enzymes observed in the study population were similar to those reported in other studies. The presence of the variant allele in the NQO1 genotype may be a risk factor for the observed hematological changes.


O benzeno é uma das substâncias mais importantes para a biomonitorização, em função do uso disseminado, da contaminação ambiental que resulta da emissão e dos efeitos sobre a saúde humana. O benzeno é classificado pela Agência Internacional de Pesquisa em Câncer (IARC) como carcinógeno conhecido em seres humanos (grupo 1) e está associado ao desenvolvimento de leucemias. Em geral, a população fica exposta a essa substância através da inalação do ar contaminado, que varia de acordo com a localização e a intensidade das fontes potenciais. A indústria petroquímica é uma das fontes mais importantes desse composto. O Município de Duque de Caxias, especificamente o Distrito de Campos Elíseos, no Estado do Rio de Janeiro, Brasil, é sede do Polo Industrial de Campos Elíseos (PICE), um conjunto de mais de 25 indústrias que inclui a segunda maior refinaria de petróleo no Brasil. A contaminação ambiental produzida pelo PICE já é conhecida, mas faltam estudos sobre o impacto na saúde da população local. Foram observadas concentrações de ácido S-fenilmercaptúrico (S-PMA) entre 0,80 e 8,01μg.g-1 creatinina na população local, aparentemente implicadas nas alterações hematológicas também observadas na população exposta. A presença quantificável do S-PMA urinário do metabolismo do benzeno está associada ao fato de 60% dos participantes apresentarem alterações hematológicas específicas, o que pode ser devido à exposição ambiental ao benzeno. As frequências alélicas e genotípicas das enzimas CYP2E1 e NQO1, observadas na população do estudo, foram semelhantes àquelas relatadas em outros estudos. A presença da variante alélica do genótipo NQO1 pode ser um fator de risco para as alterações hematológicas observadas.


El benceno es una de las sustancias más importantes susceptibles de estudio, debido a su uso significativo, la contaminación ambiental resultante de sus emisiones y sus efectos sobre la salud humana. Está clasificado por el Centro Internacional de Investigaciones sobre el Cáncer (IARC) como un conocido carcinógeno para los humanos (grupo 1) y está asociado con el desarrollo de leucemias. En general, la población está expuesta a esta sustancia por inhalación de aire contaminado, que varía según el lugar y la intensidad de las emisiones. La industria petroquímica es un de las fuentes emisoras más importantes de este compuesto. La municipalidad de Duque de Caxias, específicamente el distrito de Campos Elíseos, en Río de Janeiro, Brasil, alberga el Complejo Industrial de Campos Elíseos (PICE), un conglomerado de más de 25 industrias, que incluye la segunda mayor refinería de petróleo en Brasil. La contaminación ambiental procedente del PICE ya ha sido reconocida, pero es notable la falta de estudios respecto a su impacto en la salud de la población circundante. Se observaron en la población local concentraciones de ácido s-fenilmercaptúrico (SPMA por sus siglas en inglés) que oscilan entre los 0,80 a 8,01μg.g-1 creatinina, aparentemente relacionadas con cambios hematológicos también hallados en la población expuesta. La presencia cuantificable de SPMA en la orina, procedente del metabolismo del benceno, está asociada con el hecho de que un 60% de los participantes presenta cambios específicos hematológicos, los cuales tal vez se deben a la exposición ambiental al benceno. Las frecuencias alélicas y genotípicas del CYP2E1 y enzimas NQO1 observadas en el estudio fueron similares a las reportadas en otros estudios. La presencia de la variante alélica en el genotipo NQO1 podría ser un factor de riesgo para los cambios hematológicos observados.


Subject(s)
Humans , Male , Female , Polymorphism, Genetic/genetics , Acetylcysteine/analogs & derivatives , Benzene/adverse effects , Environmental Exposure/adverse effects , Acetylcysteine/urine , Brazil , Biomarkers/urine , Odds Ratio , Chemical Industry , Residence Characteristics/statistics & numerical data , Causality , Health Surveys/statistics & numerical data , NAD(P)H Dehydrogenase (Quinone)/analysis , NAD(P)H Dehydrogenase (Quinone)/genetics , Cytochrome P-450 CYP2E1/analysis , Cytochrome P-450 CYP2E1/genetics , Creatinine/urine , Gene Frequency/genetics , Hematologic Diseases/chemically induced
6.
Biomédica (Bogotá) ; 38(4): 555-568, oct.-dic. 2018. tab, graf
Article in Spanish | LILACS | ID: biblio-983966

ABSTRACT

Introducción. Uno de los principales factores de riesgo del carcinoma hepatocelular es el consumo crónico de alcohol. En estudios en diferentes poblaciones, se sugiere que las variantes genéticas de las enzimas que participan en el metabolismo del alcohol, como la alcohol deshidrogenasa (ADH) y la citocromo P450 (CYP2E1), estarían asociadas con riesgo de enfermedades hepáticas terminales. Objetivo. Identificar y caracterizar las variantes alélicas de los genes ADH1B, ADH1C y CYP2E1 en pacientes colombianos con diagnóstico de cirrosis y carcinoma hepatocelular. Materiales y métodos. Se incluyeron muestras de pacientes atendidos entre el 2005 y el 2007, y entre el 2014 y el 2016, en la unidad de hepatología de un hospital de Medellín. La genotipificación de las muestras se hizo mediante reacción en cadena de la polimerasa (Polymerase Chain Reaction, PCR) con análisis de los polimorfismos en la longitud de los fragmentos de restricción (Restriction Fragment Length Polymorphism, RFLP). Los resultados se compararon con los de dos grupos de control y con lo reportado en la base de datos del 1000 Genomes Project. Resultados. Se recolectaron 97 muestras de pacientes con diagnóstico de cirrosis y carcinoma hepatocelular. Los dos factores de riesgo más frecuentes fueron el consumo crónico de alcohol (18,6 %) y las colangiopatías (17,5 %). Los genotipos más frecuentes en la población de estudio fueron el ADH1B*1/1 (82 %), el ADH1C*1/1 (59 %) y el CYP2E1*C/C (84 %). Conclusiones. En este primer estudio de los polimorfismos en pacientes colombianos con diagnóstico de cirrosis y carcinoma hepatocelular, los genotipos más frecuentes fueron el ADH1B*1/1, el ADH1C*1/1 y el CYP2E1*C/C. No se observaron diferencias estadísticamente significativas en la frecuencia de los genotipos entre los casos y los controles. Se requieren estudios adicionales en población colombiana para evaluar el riesgo de la enfermedad hepática terminal por consumo crónico de alcohol y la asociación con los polimorfismos.


Introduction: One of the most important risk factors for hepatocellular carcinoma (HCC) is alcohol consumption: Studies in different populations suggest that the risk of liver disease could be associated with genetic variants of the enzymes involved in alcohol metabolism, such as alcohol dehydrogenase (ADH) and cytochrome P450 CYP2E1. Objective: To identify and characterize the allelic variants of ADH1B, ADH1C and CYP2E1 genes in Colombian patients with cirrhosis and/or HCC. Materials and methods: We included samples from patients attending the hepatology unit between 2005-2007 and 2014-2016 of a hospital in Medellin. Samples were genotyped using PCR-RFLP. We compared the results with two control groups and the 1000 Genomes Project database. Results: We collected 97 samples from patients with a diagnosis of cirrhosis and/or HCC. The two main risk factors were chronic alcohol consumption (18.6%) and cholangiopathies (17.5%). The most frequent genotypes in the study population were ADH1B*1/1 (82%), ADH1C*1/1 (59%), and CYP2E1*C/C (84%). Conclusions: This first study of polymorphisms in Colombian patients diagnosed with cirrhosis and/or HCC showed genotypes ADH1B*1/1, ADH1C*1/1 and CYP2E1*C/C as the most frequent. We found no significant differences in the genotype frequency between cases and controls. Further studies are necessary to explore the association between polymorphisms and the risk of end-stage liver disease from alcohol consumption.


Subject(s)
Alcohol Dehydrogenase , Cytochrome P-450 CYP2E1 , Carcinoma, Hepatocellular/etiology , Alleles , Genotype , Liver Cirrhosis/etiology
7.
Braz. J. Pharm. Sci. (Online) ; 54(3): e17732, 2018. tab, graf
Article in English | LILACS | ID: biblio-974392

ABSTRACT

Overconsumption of alcohol leads to alcoholic liver disease (ALD). Natural compounds have been investigated previously for their hepatoprotective activities against liver injury. This study investigated the protective effect of Alhagi sparsifolia on ALD. Alcohol was administered to mice for three consecutive days; either alone or in combination with Alhagi sparsifolia extract (150, 300, 600 mg/kg). Serum aspartate aminotransferase and alanine transaminase as biomarkers of liver injury, the content of malonaldehyde, hydrogen peroxide (H2O2) and glutathione which indicated the redox status of liver and the antioxidant enzyme activity of super oxide dismutase were detected, respectively. Moreover, the expression of protein cytochrome P450 2E1 (CYP2E1) the key enzyme of alcohol metabolism, and also tested by western blot experiment. Subsequently, the mRNA levels of inflammatory factors including TNF- α and TLR4 was determined real-time PCR. Results showed that Alhagi sparsifolia significantly alleviated alcohol-induced liver injury by reducing serum ALT and AST, inhibiting MDA and H2O2 content, increasing SOD, and GSH level in the liver (P< 0.05). In addition, the Alhagi sparsifolia treatment inhibited the expression of CYP2E1 (P< 0.05). The results suggest that Alhagi sparsifolia could be a promising natural substance for ameliorating acute alcohol-induced oxidative stress and hepatic injury


Subject(s)
Animals , Female , Rats , Fabaceae/adverse effects , Liver Diseases, Alcoholic , Plant Extracts/therapeutic use , Oxidative Stress , Cytochrome P-450 CYP2E1 , Liver Cirrhosis, Alcoholic/drug therapy , Antioxidants/pharmacology
8.
Article in English | WPRIM | ID: wpr-713617

ABSTRACT

The liver is an essential organ for the detoxification of exogenous xenobiotics, drugs and toxic substances. The incidence rate of non-alcoholic liver injury increases due to dietary habit change and drug use increase. Our previous study demonstrated that Ecklonia stolonifera (ES) formulation has hepatoprotective effect against alcohol-induced liver injury in rat and tacrine-induced hepatotoxicity in HepG2 cells. This present study was designated to elucidate hepatoprotective effects of ES formulation against carbon tetrachloride (CCl₄)-induced liver injury in Sprague Dawley rat. Sixty rats were randomly divided into six groups. The rats were treated orally with ES formulation and silymarin (served as positive control, only 100 mg/kg/day) at a dose of 50, 100, or 200 mg/kg/day for 21 days. Seven days after treatment, liver injury was induced by intraperitoneal injection of CCl₄ (1.5 ml/kg, twice a week for 14 days). The administration of CCl₄ exhibited significant elevation of hepatic enzymes (like AST and ALT), and decrease of antioxidant related enzymes (superoxide dismutase, glutathione peroxidase and catalase) and glutathione. Then, it leaded to DNA damages (8-oxo-2′-deoxyguanosine) and lipid peroxidation (malondialdehyde). Administration of ES formulation inhibited imbalance of above factors compared to CCl₄ induced rat in a dose dependent manner. Real time PCR analysis indicates that CYP2E1 was upregulated in CCl₄ induced rat. However, increased gene expression was compromised by ES formulation treatment. These findings suggests that ES formulation could protect hepatotoxicity caused by CCl₄ via two pathways: elevation of antioxidant enzymes and normalization of CYP2E1 enzyme.


Subject(s)
Animals , Carbon Tetrachloride , Cytochrome P-450 CYP2E1 , DNA Damage , Feeding Behavior , Gene Expression , Glutathione , Glutathione Peroxidase , Hep G2 Cells , Incidence , Injections, Intraperitoneal , Lipid Peroxidation , Liver , Rats , Rats, Sprague-Dawley , Real-Time Polymerase Chain Reaction , Silymarin , Xenobiotics
9.
Mem. Inst. Oswaldo Cruz ; 111(12): 757-764, Dec. 2016. graf
Article in English | LILACS | ID: biblio-829258

ABSTRACT

We evaluated the effects of a non-hepatotropic parasite infection (Taenia crassiceps) on the outcome of acetaminophen-induced acute liver failure in mice. Uninfected and T. crassiceps infected mice orally received either 300 mg/kg acetaminophen or water as vehicle (n = 5 per group). Survival analysis, hepatocyte necrosis, alanine aminotransferase (ALT) levels, CYP2E1 protein, interleukin (IL-) 5, and IL-6 were assessed for all groups. All infected mice died within 16 h after exposure to acetaminophen (Tc+APAP group), whereas only one-third of uninfected animals exposed to acetaminophen (APAP group) died. Uninfected (Control group) and infected (Tc group) mice that received the vehicle showed no liver damage. Tc+APAP mice exhibited massive liver necrosis characterised by marked balloning degeneration of hepatocytes and higher serum ALT compared to Control, Tc, and APAP animals. Liver tissue from Tc+APAP mice also displayed increased expression of CYP2E1 protein and higher mRNA and protein levels of IL-5 and IL-6 compared to the other groups. These findings suggest that non-hepatotropic parasite infections may increase mortality following acute liver failure by promoting hepatocyte necrosis via IL-5 and IL-6-dependent CYP2E1 overproduction. This study identifies new potential risk factors associated with severe acute liver failure in patients.


Subject(s)
Animals , Female , Acetaminophen , Analgesics, Non-Narcotic , Liver Failure, Acute , Taeniasis/parasitology , Acetaminophen/administration & dosage , Alanine Transaminase/blood , Analgesics, Non-Narcotic/administration & dosage , Biomarkers/blood , Cytochrome P-450 CYP2E1/biosynthesis , Cytochrome P-450 CYP2E1/blood , Disease Models, Animal , Hepatocytes/parasitology , Hepatocytes/pathology , Interleukin-5/blood , Interleukin-6/blood , Liver Failure, Acute/chemically induced , Liver Failure, Acute/mortality , Liver Failure, Acute/parasitology , Liver Failure, Acute/pathology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Taeniasis/pathology
10.
Rev. colomb. gastroenterol ; 31(1): 27-35, ene.-mar. 2016. ilus, tab
Article in Spanish | LILACS | ID: lil-781927

ABSTRACT

La cirrosis hepática es la tercera causa de muerte alrededor del mundo que es atribuible al consumo de alcohol. Más del 80% de los consumidores crónicos de alcohol desarrollan esteatosis y entre el 20% al 40% presentan otras complicaciones como fibrosis, hepatitis alcohólica y cirrosis; sin embargo, no todos los individuos con consumo crónico de alcohol desarrollan cirrosis, en parte debido al componente genético de cada individuo. El grado de actividad de las enzimas que metabolizan el alcohol está influenciado por polimorfismos presentes en los genes que codifican para estas enzimas, y corresponde a uno de los factores determinantes para el desarrollo de una hepatopatía terminal en respuesta al consumo de alcohol. Entre las enzimas implicadas en el metabolismo del alcohol están la alcohol deshidrogenasa (ADH), el citocromo P450 2E1 (CYP2E1) y la acetaldehído deshidrogenasa (ALDH), de las cuales se ha reportado que la mayor actividad de ADH y CYP2E1 y la menor actividad de ALDH pueden conferir riesgo en algunas poblaciones por la acumulación de acetaldehído, el cual es tóxico para el organismo. Se realizó una revisión en la literatura de los principales aspectos del metabolismo del alcohol y polimorfismos (genotipos) de enzimas que intervienen en el metabolismo del alcohol como factor de riesgo. Esto se hizo mediante la búsqueda de material bibliográfico a través de la base de datos PubMed desde 1990 hasta el 2013 utilizando las palabras claves alcohol liver disease, ADH, ALDH, CYP2E1 y polymorphism.


Liver cirrhosis is the third most common cause of death attributable to alcohol consumption throughout the world. More than 80% of chronic drinkers develop steatosis, and 20% to 40% develop other complications such as fibrosis, alcoholic hepatitis and cirrhosis. However, not everyone who chronically consumes alcohol develops cirrhosis. This is partly because of the genetic component of each individual. The level of activity of the enzymes that metabolize alcohol is influenced by polymorphisms of the genes that coding for these enzymes. This is one of the determining factors in the development of terminal liver disease in response to alcohol consumption. Among the enzymes involved in alcohol metabolism are alcohol dehydrogenase (ADH), cytochrome P450 2E1 (CYP2E1) and acetaldehyde dehydrogenase (ALDH). It has been reported that higher levels of activity of ADH and CYP2E1 and lower levels of activity of ALDH may be risk factors in some populations for accumulation of acetaldehyde which is toxic for the organism. This literature review covers the most important aspects of alcohol metabolism including polymorphisms (genotypes) of enzymes involved in the metabolism of alcohol as a risk factor. A search through the PubMed database from 1990 to be held 2013 was conducted using the keywords alcoholic liver disease, ADH, ALDH, CYP2E1, and polymorphism.


Subject(s)
Humans , Aldehyde Dehydrogenase, Mitochondrial , Cytochrome P-450 CYP2E1 , Inappropriate ADH Syndrome , Liver Diseases, Alcoholic , Polymorphism, Genetic
11.
Braz. j. med. biol. res ; 49(11): e5238, 2016. graf
Article in English | LILACS | ID: lil-797893

ABSTRACT

Early nutrition plays a long-term role in the predisposition to chronic diseases and influences the metabolism of several drugs. This may happen through cytochromes P450 (CYPs) regulation, which are the main enzymes responsible for the metabolism of xenobiotics. Here, we analyzed the effects of maternal protein restriction (MPR) on the expression and activity of hepatic offspring’s CYPs during 90 days after birth, using Wistar rats as a mammal model. Hepatic CYP1A1, CYP1A2, CYP2B1, CYP2B2 and CYP2E1 mRNA and protein expression, and associated catalytic activities (ECOD, EROD, MROD, BROD, PROD and PNPH) were evaluated in 15-, 30-, 60-, and 90-day-old offspring from dams fed with either a 0% protein (MPR groups) or a standard diet (C groups) during the 10 first days of lactation. Results showed that most CYP genes were induced in 60- and 90-day-old MPR offspring. The inductions detected in MPR60 and MPR90 were of 5.0- and 2.0-fold (CYP1A2), 3.7- and 2.0-fold (CYP2B2) and 9.8- and 5.8– fold (CYP2E1), respectively, and a 3.8-fold increase of CYP2B1 in MPR90. No major alterations were detected in CYP protein expression. The most relevant CYP catalytic activities’ alterations were observed in EROD, BROD and PNPH. Nevertheless, they did not follow the same pattern observed for mRNA expression, except for an induction of EROD in MPR90 (3.5-fold) and of PNPH in MPR60 (2.2-fold). Together, these results suggest that MPR during lactation was capable of altering the expression and activity of the hepatic CYP enzymes evaluated in the offspring along development.


Subject(s)
Animals , Female , Rats , Cytochrome P-450 Enzyme System/metabolism , Diet, Protein-Restricted , Lactation/metabolism , Liver/enzymology , Aryl Hydrocarbon Hydroxylases/metabolism , Cytochrome P-450 CYP1A1/metabolism , Cytochrome P-450 CYP1A2/metabolism , Cytochrome P-450 CYP2B1/metabolism , Cytochrome P-450 CYP2E1/metabolism , Models, Animal , Rats, Wistar , Steroid Hydroxylases/metabolism , Time Factors
12.
Acta Pharmaceutica Sinica ; (12): 153-156, 2016.
Article in Chinese | WPRIM | ID: wpr-320001

ABSTRACT

The regulation mechanism of arecoline on rat hepatic CYP2E1 was studied in vivo. After oral administration of arecoline hydrobromide (AH; 4, 20 and 100 mg x kg(-1) x d(-1)) to rats for one week, the hepatic CYP2E1 mRNA level remained unchanged, but the hepatic CYP2E1 protein content was dose-dependently increased. Additionally, although the hepatic CYP2E1 activity was induced by AH treatment, the induction was attenuated with the increase in dosage. The results indicate that the effect of arecoline on rat hepaticdoes not involve transcriptional activation of the gene, but largely involves the stabilization of CYP2E1 protein against degradation or increased efficiency of CYP2E1 mRNA translation, and additionally involve the post- ranslational modification of CYP2E1 protein. Furthermore, the CYP2E1 response is fairly equal among the different species, the induction of rat hepatic CYP2E1 by arecoline suggests that there is a risk of metabolic interaction among the substrate drugs of CYP2E1 in betel-quid use human.


Subject(s)
Animals , Arecoline , Pharmacology , Cytochrome P-450 CYP2E1 , Metabolism , Cytochrome P-450 CYP2E1 Inducers , Pharmacology , Humans , Liver , Metabolism , RNA, Messenger , Rats
13.
Natural Product Sciences ; : 231-237, 2016.
Article in English | WPRIM | ID: wpr-146023

ABSTRACT

Prolonged alcohol consumption causes alcoholic liver damage due to the generation of reactive oxygen species, the accumulation of fatty acids, and an increase in inflammatory cytokines in the liver. In this study, the protective effect of a fruit extract of Paeonia anomala (FEPA) against chronic alcohol-induced liver damage was evaluated in Sprague-Dawley rats fed an ethanol or a control Lieber-DeCarli diet for 5 weeks to induce alcoholic liver damage. FEPA (50, 25, and 10 mg/kg body weight/day) as well as the reference control silymarin (25 mg/kg body weight/day) were administered along with the ethanol diet. FEPA protected against increases in alanine aminotransferase and aspartate aminotransferase in serum and attenuated alcohol-induced increases in triglycerides, tumor necrosis factor alpha, thiobarbituric acid-reactive substances, and cytochrome P450 2E1 enzyme activity in the liver compared with the group treated with ethanol only. Anti-oxidative defenses such as the total glutathione level and glutathione peroxidase activity were increased by FEPA treatment. These results suggest that FEPA exerts protective effects against chronic alcohol-induced liver damage by attenuating hepatosteatosis and pro-inflammatory cytokine production and enhancing anti-oxidative defense mechanisms in the liver.


Subject(s)
Alanine Transaminase , Alcohol Drinking , Alcoholics , Animals , Aspartate Aminotransferases , Cytochrome P-450 CYP2E1 , Cytokines , Defense Mechanisms , Diet , Ethanol , Fatty Acids , Fruit , Glutathione , Glutathione Peroxidase , Humans , Liver , Paeonia , Rats , Rats, Sprague-Dawley , Reactive Oxygen Species , Silymarin , Triglycerides , Tumor Necrosis Factor-alpha
14.
Article in Chinese | WPRIM | ID: wpr-350530

ABSTRACT

<p><b>OBJECTIVE</b>To investigate the cytochrome P450 2E1 (CYP2E1) RsaI/PstI and DraI polymorphisms in workers exposed to benzene.</p><p><b>METHODS</b>A cross-sectional survey was carried out. A total of 71 workers exposed to benzene were included in observation group and the same number of people without occupational benzene exposure were included in control group. Blood samples from the two groups were collected and genotyping for CYP2E1 RsaI/PstI and DraI were conducted using the polymerase chain reaction-restriction fragment length polymorphism.</p><p><b>RESULTS</b>There were no significant differences in CYP2E1 DraI genotype and allele distributions between the observation group and the control group (χ² = 2.374, P > 0.05; χ² = 2.113, P > 0.05). Significant differences in CYP2E1 RsaI/PstI genotype and allele distributions between the two groups were observed (χ² = 9.129, P < 0.01; χ² = 6.028, P < 0.05).</p><p><b>CONCLUSION</b>Mutations at CYP2E1 RsaI/PstI can enhance the expression of CYP2E1 and this suggests individuals with the mutated gene have increased susceptibility to chronic benzene poisoning.</p>


Subject(s)
Alleles , Benzene , Poisoning , Cross-Sectional Studies , Cytochrome P-450 CYP2E1 , Genetics , Metabolism , Genetic Predisposition to Disease , Genotype , Humans , Poisoning , Genetics , Polymerase Chain Reaction , Polymorphism, Genetic , Genetics , Polymorphism, Restriction Fragment Length
15.
Article in Chinese | WPRIM | ID: wpr-305301

ABSTRACT

The main objective of this research is to investigate the effects of astragaloside IV, calycosin separately glucoside, formononetin on oxidative stress in Chang Liver cells induced by H2O2. In the experiments, Chang Liver cells (a kind of normal human hepatocytes) were used as the research object, bifendate which has a clear hepatoprotective effect was used as the positive control drug, then the oxidative damage model of Chang Liver cells were established by H2O2. Cells were divided into six groups: blank control group, oxidative stress group, astragaloside IV group, calycosin separately glucoside group, formononetin group and positive control group. Then endogenous antioxidant system related indexes were detected by micro plate and colorimetric method; intracellular reactive oxygen species (ROS) were detected by DCFH-DA fluorescent probe; and the expressions of CYP2E1 were evaluated by liver microsomes, mRNA, and protein, respectively with spectrophotometry, Real-time PCR method, and Western blot technique. Results showed that H2O2 decreased antioxidant activity, and increased ROS level and expression of CYP2E1. The above oxidative stress status had been changed with protections of the three components of Astragalus membranaceus (compared with oxidative stress group, P < 0.05, P < 0.01), which taken as a whole had equivalent effects as the drug of positive control group( bifendate). Taken together, three Astragalus membranaceus ingredients all had significant or extremely significant inhibiting effects on oxidative damaged Chang Liver cells which were induced by H2O2, and the oxidative damage of Chang Liver cells had been relieved.


Subject(s)
Astragalus propinquus , Chemistry , Cells, Cultured , Cytochrome P-450 CYP2E1 , Metabolism , Humans , Isoflavones , Pharmacology , Liver , Oxidative Stress , Reactive Oxygen Species , Metabolism , Saponins , Pharmacology , Triterpenes , Pharmacology
16.
Article in Chinese | WPRIM | ID: wpr-288035

ABSTRACT

<p><b>OBJECTIVE</b>To assess the association of cytochrome P450 gene single nucleotide polymorphisms (SNPs) with susceptibility to gout in ethnic Han males from coastal regions of Shandong province.</p><p><b>METHODS</b>Four hundred and eighty male patients with gout and 480 healthy male controls were included. Genotyping was carried out with a custom Illumina GoldenGate Genotyping assay to detect SNP rs2275620 of CYP2C8 gene, SNP rs2070676 of CYP2E1 gene, SNP rs837395 of CYP4B1 gene, and SNP rs194150 of TBXAS1 gene. The association was assessed with chi-square test.</p><p><b>RESULTS</b>No significant difference has been found between the two groups in regard to the genotypic and allelic frequencies of the TT, AT, AA genotypes and A, T alleles of the SNP rs2275620 of the CYP2C8 gene (P=0.88; P=0.97), the CC, CG, GG genotypes and C,G alleles of SNP rs2070676 of the CYP2E1 gene (P=0.24; P=0.09), the TT, AT, AA genotypes and A, T alleles of SNP rs837395 of the CYP4B1 (P=0.88; P=0.97), and TT, AT, AA genotypes and the A,T alleles of SNP rs194150 of TBXAS1 gene (P=0.15; P=0.06).</p><p><b>CONCLUSION</b>This study has identified no association of SNP loci rs2275620(A/T) of CYP2C8, rs2070676(C/G) of CYP2E1, rs837395(A/T) of CYP4B1 and rs194150(A/T) of TBXAS1 with gout in ethnic Han males from coastal regions in Shandong province. However, our result needs to be replicated in larger sets of patients collected from other regions and populations.</p>


Subject(s)
Adult , Aryl Hydrocarbon Hydroxylases , Genetics , Asian Continental Ancestry Group , Ethnology , Genetics , China , Ethnology , Cytochrome P-450 CYP2C8 , Genetics , Cytochrome P-450 CYP2E1 , Genetics , Disease Susceptibility , Female , Gout , Ethnology , Genetics , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide , Thromboxane-A Synthase , Genetics
17.
Article in Chinese | WPRIM | ID: wpr-246094

ABSTRACT

Rats were continuously given different doses of water extract of Polygonum multiflorum (1, 10 g x kg(-1)) for 7 days to prepare liver microsomes. Cocktail in vitro incubation approach and Real-time quantitative PCR technology were used to observe the effect of water extract of P. multiflorum on CYP450 enzymatic activities and mRNA expressions in rat liver. Compared with the blank control group, both 1, 10 g x kg(-1) water extract of P. multiflorum treated groups showed significant inhibitions in CYP2E1 enzymatic activities and mRNA expressions (enzymatic activities of CYP2E1, P < 0.01; mRNA expression of CYP2E1, P < 0.05 in 1 g x kg(-1) group, P < 0.01 in 10 g x kg(-1) group). They revealed a significant increase in the enzymatic activity of CYP3A1 (P < 0.01), but without significant change in mRNA expressions. The 10 g x kg(-1) group showed a significant inhibition in CYP1A2 enzymatic activities and mRNA expressions in rat livers (P < 0.01).


Subject(s)
Animals , Cytochrome P-450 CYP1A2 , Genetics , Metabolism , Cytochrome P-450 CYP2E1 , Genetics , Metabolism , Cytochrome P-450 Enzyme Inhibitors , Drugs, Chinese Herbal , Liver , Male , Microsomes, Liver , Polygonum , Chemistry , RNA, Messenger , Genetics , Metabolism , Rats , Rats, Sprague-Dawley
18.
Indian J Cancer ; 2014 Apr-Jun; 51(2): 154-158
Article in English | IMSEAR | ID: sea-154320

ABSTRACT

AIM: The aim of the study to find out role of CYP2E1 genetic polymorphism in development of oral leukoplakia among tobacco users in North Indian population, this study was carried out at Department of Oral and Maxillofacial Pathology, King George’s Medical University, Lucknow, UP. STUDY DESIGN: Study include a total of 105 leukoplakia patients were genotyped for CYP2E1 polymorphism (93 males and 12 females; mean age ± SD: 47.5 ± 10.6) and 96 unrelated healthy controls (85 males and 11 females; mean age ± SD: 49 ± 11.1). All the patients had either reported for treatment of leukoplakia or were diagnosed with leukoplakia during routine oral examination. RESULTS: A total of 105 leukoplakia patients and 96 controls were included in the study. The mean age of leukoplakia patients and control were 47 ± 10 and 51 ± 10 years respectively. The exclusive smokers comprised 62 (59%) leukoplakia patients and 53 (53%) controls. The exclusive smokeless tobacco users were 16 (15%) in leukoplakia patients and 27 (28%) in controls groups, while 27 (26%) leukoplakia patients and 16 (17%) controls have both types (smoking as well as smoke less) of tobacco habits simultaneously. Range of life time smoking exposure in leukoplakia and controls were (5‑80 PY in both groups) but the mean smoking exposure in both groups were (leukoplakia: 28 ± 21.8 PY, control: 27: ±17 PY). But the mean smokeless tobacco dose in two groups were (leukoplakia: 150 ± 175 CY, controls: 137 ± 110 CY). CONCLUSION: All the results demonstrate an association between CYP2E1 genetic polymorphism and leukoplakia risk, premalignant lesion. It indicates that the CYP2E1 polymorphism, singly showed a protection towards the oral leukoplakia. Independent confirmation of this finding is required, and additional examination of the joint effect of CYP2E1genotype and other non‑tobacco‑related exposures is needed before more conclusive interpretation of our results can be made. This study demonstrates the importance of genetic variations in CYP2E1genes in susceptibility towards oral leukoplakia and it is conceivable that these variants will interact with environmental carcinogens and possibly some combinations of these genotypes will be at a high risk to oral leukoplakia.


Subject(s)
Adult , Cytochrome P-450 CYP2E1/genetics , Female , Genetic Predisposition to Disease , Genotype , Humans , India , Leukoplakia, Oral/genetics , Male , Middle Aged , Polymerase Chain Reaction , Polymorphism, Restriction Fragment Length , Tobacco/adverse effects
19.
Chinese Journal of Hepatology ; (12): 757-762, 2014.
Article in Chinese | WPRIM | ID: wpr-337104

ABSTRACT

<p><b>OBJECTIVE</b>To investigate the effects of glucagon-like peptide-1 (GLP-1) on liver oxidative stress injury using a rat model of non-alcoholic fatty liver disease.</p><p><b>METHODS</b>Sixty male Sprague-Dawley rats were fed 12 weeks of either a diet of normal chow (NC), for use as controls (n =15) or high-fat chow (HF), for use as models (n =45).The NC rats were administered normal saline, while the HF rats were treated with either normal saline (NS), for use as untreated model controls (n =10), low-dose GLP-1 (LG, 50 mutg/kg; n =10), mid-dose GLP-1 (MG, 100 mutg/kg; n =10), or high-dose GLP-1 (HG, 200 mug/kg; n =10); all treatments lasted for 4 weeks.The rats' weight, levels of serum biochemical markers (triglycerides, total cholesterol, high-density lipoproteincholesterol, low-density lipoprotein-cholesterol, alanine arninotransferase, and aspartate aminotransferase), levels of superoxide dismutase (SOD) and malondialdehyde (MDA), and expression of CYP2E1 mRNA and protein in liver homogenates were measured.The F test, t-test, least significant difference test and Dunnett's T3 test were used for statistical analyses.</p><p><b>RESULTS</b>Compared with the NC group, the rars in the NS group showed significantly lower SOD (165.81 ± 11.64 vs.192.89 ± 16.53 U/mg, P < 0.05), significantly higher MDA (7.30 ± 1.79 vs.3.10 ± 1.30 nmol/ mg, P < 0.05), and significantly higher expressions of CYP2E1 mRNA and protein (both P < 0.05).After GLP1 treatment, the rats in the LG, MG and HG groups showed increased levels of SOD (compared to the NS group; 171.44 ± 9.80 vs.177.66 ± 14.77 vs.186.17 ± 15.43 U/mg; only the HG group had P < 0.05), significantly decreased levels of MDA (compared to the NS group; 5.16 ± 1.45 vs.4.08 ± 1.22 vs.3.31 ± 1.14 nmol/mg; all P < 0.05], and decreased levels of CYP2E1 mRNA and protein expressions (CYP2E1 mRNA:only the HG group had P < 0.05; CYP2E1 protein: both the MG and HG groups had P < 0.05).</p><p><b>CONCLUSION</b>GLP-1 treatment can improve oxidative stress injury, suggesting its potential as a therapeutic agent for non-alcoholic fatty liver disease.</p>


Subject(s)
Animals , Aspartate Aminotransferases , Cytochrome P-450 CYP2E1 , Glucagon-Like Peptide 1 , Metabolism , Male , Malondialdehyde , Non-alcoholic Fatty Liver Disease , Metabolism , Oxidative Stress , Rats , Rats, Sprague-Dawley , Superoxide Dismutase , Triglycerides
20.
Article in Chinese | WPRIM | ID: wpr-289812

ABSTRACT

<p><b>OBJECTIVE</b>To investigate the effects of trichloroethylene (TCE) toxicity on the normal human liver cells (L02 cells) and hepatocytes with CYP2E1 gene overexpression which was constructed through molecular cloning technology in our laboratory, then to explore the roles of CYP2E1 gene in TCE toxicity.</p><p><b>METHODS</b>L02 cells and hepatocytes with CYP2E1 overexpression were treated with various doses of TCE (0,0.25, 0.5, 1.0, 2.0, 4.0 mmol/L) for 12h, the expression of apoptosis genes (Bcl-2, Caspase-3, Caspase-8, Caspase-9) and oncogenes (c-fos, c-myc, k-ras, p53) were determined by real-time fluorescent PCR.</p><p><b>RESULTS</b>Bcl-2 mRNA expression levels increased significantly in normal liver cells and CYP2E1-overexpressing cells after TCE treatment, Bcl-2 levels were 20%∼50%higher in CYP2E1-overexpressing cells than in L02 liver cells at doses of 0.25∼2.0 mmol/L TCE. Caspase-3, Caspase-8 and caspase-9 mRNA expression increased by 30%∼600% in CYP2E1-overexpressing cells at doses of 0.5∼4.0 mmol/L TCE when compared with L02 cells (P < 0.01). Additionally, c-fos, k-ras and c-myc mRNA expression levels were 25%∼120% higher in CYP2E1-overexpressing cells than in L02 cells (P < 0.01), p53 mRNA expression levels were lower 10%∼50% in CYP2E1-overexpressing cells than in L02 cells (P < 0.05 or P < 0.01).</p><p><b>CONCLUSIONS</b>There were significant differences for apoptosis gene and oncogene expression levels between normal liver cells and CYP2E1-overexpressing cells after they were treated with TCE, these findings indicated that CYP2E1 might play an important role in TCE metabolism in vivo.</p>


Subject(s)
Apoptosis Regulatory Proteins , Caspase 3 , Caspase 8 , Caspase 9 , Cytochrome P-450 CYP2E1 , Genetics , Gene Expression , Hepatocytes , Humans , Liver , Proto-Oncogenes , Genetics , RNA, Messenger , Trichloroethylene , Toxicity
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