Dexmedetomidine attenuates acute alcoholic hepatic injury in mice / 中国病理生理杂志

AIM:To investigate the effects of dexmedetomidine (DEX) on acute alcoholic hepatic injury in mice and to explore the possible mechanisms .METHODS:Kunming mice (n=50) were randomly divided into 5 groups (n=10):normal saline control (NS) group, acute alcoholic hepatic injury model (E) group, low-dose (10μg/kg) DEX (E+L) group, medium-dose (50 μg/kg) DEX (E+M) group and high-dose (100 μg/kg) DEX (E+H) group.The animals were sacrificed at 6 h after gavage of alcohol or normal saline .The levels of alanine aminotransferase ( ALT) , as-partate aminotransferase (AST), triglyceride (TG), malondialdehyde (MDA), glutathione (GSH) and superoxide dis-mutase ( SOD) were measured .The livers were removed for evaluation of histological characteristics and determining the content of tumor necrosis factor-α( TNF-α) amd interleukin-1β( IL-1β) in the liver tissues by ELISA .The expression levels of cytochrome P4502E1 (CYP2E1) and nuclear factor -κB (NF-κB) in the liver tissues were evaluated by Western blot.RESULTS:Compared with NS group, the levels of ALT, AST and TG were obviously increased in E group , which were obviously decreased in E +M and E+H groups.Compared with NS group, the levels of TNF-α, IL-1βand MDA were obviously increase in E group , which were obviously decreased in E +M and E+H groups.Compared with NS group, the activity of SOD and the content of GSH were obviously decreased in E group , which were obviously increased in E +M and E+H groups.Compared with NS group, the expression of CYP2E1 and NF-κB was obviously increase in E group , which was obviously decreased in E +M and E+H groups.Compared with NS group , ethanol induced marked liver histo- logical injury, which was less pronounced in E +M and E+H groups.CONCLUSION: DEX has a protective effect on mouse liver with acute alcoholic injury by the involvement in the processes of antioxidation and antiinflammation , and its mechanism may be associated with the inhibition of CYP 2E1 and NF-κB expression.

Dexmedetomidine attenuates acute alcoholic hepatic injury in mice / 中国病理生理杂志

AIM:To investigate the effects of dexmedetomidine (DEX) on acute alcoholic hepatic injury in mice and to explore the possible mechanisms .METHODS:Kunming mice (n=50) were randomly divided into 5 groups (n=10):normal saline control (NS) group, acute alcoholic hepatic injury model (E) group, low-dose (10μg/kg) DEX (E+L) group, medium-dose (50 μg/kg) DEX (E+M) group and high-dose (100 μg/kg) DEX (E+H) group.The animals were sacrificed at 6 h after gavage of alcohol or normal saline .The levels of alanine aminotransferase ( ALT) , as-partate aminotransferase (AST), triglyceride (TG), malondialdehyde (MDA), glutathione (GSH) and superoxide dis-mutase ( SOD) were measured .The livers were removed for evaluation of histological characteristics and determining the content of tumor necrosis factor-α( TNF-α) amd interleukin-1β( IL-1β) in the liver tissues by ELISA .The expression levels of cytochrome P4502E1 (CYP2E1) and nuclear factor -κB (NF-κB) in the liver tissues were evaluated by Western blot.RESULTS:Compared with NS group, the levels of ALT, AST and TG were obviously increased in E group , which were obviously decreased in E +M and E+H groups.Compared with NS group, the levels of TNF-α, IL-1βand MDA were obviously increase in E group , which were obviously decreased in E +M and E+H groups.Compared with NS group, the activity of SOD and the content of GSH were obviously decreased in E group , which were obviously increased in E +M and E+H groups.Compared with NS group, the expression of CYP2E1 and NF-κB was obviously increase in E group , which was obviously decreased in E +M and E+H groups.Compared with NS group , ethanol induced marked liver histo- logical injury, which was less pronounced in E +M and E+H groups.CONCLUSION: DEX has a protective effect on mouse liver with acute alcoholic injury by the involvement in the processes of antioxidation and antiinflammation , and its mechanism may be associated with the inhibition of CYP 2E1 and NF-κB expression.

Characterization of polymorphisms of genes ADH2, ADH3, ALDH2 and CYP2E1 and relationship to the alcoholism in a Colombian population / Caracterización de polimorfismos de los genes ADH2, ADH3, ALDH2 y CYP2E1 y su relación con el alcoholismo en una población colombiana

Objective: Identify and characterize polymorphisms of genes ADH2, ADH3, ALDH2 and CYP2E1 in a Colombian population residing in the city of Bogotá and determine its possible relationship to the alcoholism. Methods: ADH2, ADH3, ALDH2, and CYP2E1 genotypes a population of 148 individuals with non-problematic alcohol and 65 individuals with alcoholism were determined with TaqMan probes and PCR-RFLP. DNA was obtained from peripheral blood white cells. Results: Significant difference was found in family history of alcoholism and use of other psychoactive substances to compare alcoholics with controls. When allelic frequencies for each category (gender) were considered, frequency of A2 allele carriers in ADH2 was found higher in male patients than controls. In women, the relative frequency for c1 allele in CYP2E1 was lower in controls than alcoholics. The ALDH2 locus is monomorphic. No significant differences in allele distributions of the loci examined to compare two populations were observed, however when stratifying the same trend was found that these differences tended to be significant. Conclusions: This study allows us to conclude the positive association between family history of alcoholism and alcoholism suggesting that there is a favourable hereditary predisposition. Since substance dependence requires interaction of multiple genes, the combination of genotypes ADH2*2, CYP2E1*1 combined with genotype homozygous ALDH2*1 found in this study could be leading to the population to a potential risk to alcoholism.

Objetivo: Identificar y caracterizar los polimorfismos de los genes ADH2, ADH3, ALDH2 y CYP2E1 de colombianos residentes en la ciudad de Bogotá y determinar su posible relación con el alcoholismo. Métodos: Se determinaron los genotipos ADH2, ADH3, ALDH2 y CYP2E1 a una población de 148 individuos con un consumo no problemático de alcohol y 65 individuos con alcoholismo. La genotipificación se realizó con sondas TaqMan y PCR-RFLP, el ADN se obtuvo de células blancas de sangre periférica. Resultados: Se encontró diferencia significativa en la historia familiar de alcoholismo y el uso de otras sustancias psicoactivas. Cuando se consideraron frecuencias alélicas para cada categoría (género), la frecuencia de portadores del alelo A2 en ADH2 se encontró mayor en los pacientes masculinos que los controles. En las mujeres, la frecuencia relativa para el alelo C1 de CYP2E1 fue menor en controles que en alcohólicos. El locus ALDH2 es monomórfico. No se observaron diferencias significativas en las distribuciones alélicas de los loci examinadas al comparar las dos poblaciones, sin embargo al estratificar las mismas se encontró una tendencia a que esas diferencias fueran significativas. Conclusiones: Este estudio nos permite concluir la asociación positiva entre historia familiar de alcoholismo y el alcoholismo, lo que sugiere que existe una predisposición hereditaria favorable. Dado que la dependencia de sustancias requiere la interacción de múltiples genes como ADH2*2, CYP2E1*1 combinado con el genotipo homocigótico ALDH2*1 hallados en este estudio podría estar llevando a la población a un riesgo potencial hacia el alcoholismo.

Hepatotoxicity in Rats Treated with Dimethylformamide or Toluene or Both

The effects of toluene in dimethylformamide (DMF)-induced hepatotoxicity were investigated with respect to the induction of cytochrome P-450 (CYP) and the activities of related enzymes. The rats were treated intraperitoneally with the organic solvents in olive oil (Single treatment groups: 450 [D1], 900 [D2], 1,800 [D3] mg DMF, and 346 mg toluene [T] per kg of body weight; Combined treatment groups: D1+T, D2+T, and D3+T) once a day for three days, while the control group received just the olive oil. Each group consisted of 4 rats. The activities of the xenobiotic metabolic enzymes and the hepatic morphology were assessed. The immunoblots indicated that the expression of CYP2E1 was considerably enhanced depending on the dosage of DMF and the CYP2E1 blot densities were significantly increased after treatment with both DMF and toluene, compared to treatment with DMF alone. The activities of glutathione-S-transferase and glutathione peroxidase were either decreased or remained unaltered after treatment with DMF and toluene, whereas the lipid peroxide levels were increased with increasing dosage of DMF and toluene. The liver tissue in the D3 group (1,800 mg/kg of DMF) showed signs of microvacuolation in the central vein region and a large necrotic zone around the central vein, in rats treated with both DMF (1,800 mg/kg) and toluene (D3T). These results suggest that the expression of CYP2E1 is induced by DMF and enhanced by toluene. These changes may have facilitated the accelerated formation of N-methylformamide (NMF) from toluene, and the generated NMF may directly induce liver damage.

Research on the relationship between ALDH2 and CYP2E1 gene polymorphism and alcoholic liver disease in Han people / 重庆医科大学学报

Objective:To explore the relationship between genetic polymorphism of ALDH2 and CYP2E1 and alcoholic liver disease(ALD) in Han people. Methods:PCR-RFLP was used to detect the frequencies of gene types and allele of ALDH and CYP2E1 in health control group(45 cases),ALD group(48 cases),alcohol dependent group(38 cases) and non-ALD(NALD) group(42 cases),and the frequencies were compared. Results:The difference of the frequencies of ALDH2*1 and ALDH2*2 had statistic significance between health control group and ALD group,and between in ALD group and NALD group(P

Study on the association between CYP2E1 enzymes and susceptibility of alcoholic liver disease / 中国实用内科杂志

Objective To investigate the correlation between the CYP2E1 enzymes and alcoholic liver disease.Methods Polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP)method was used to determine polymorphism of CYP2E1.A case control study of 183 subjects was carried out including 40 cases of alcoholic liver disease,40 alcohol dependent group,40 nonalcoholic liver disease and 63 controls.Results The frequency of B genotype or C2 allele gene was significantly higher in alcoholic liver disease than in control(P

Serum Level of Carbohydrate Deficient Transferrin and Genetic Polymorphisms of Cytochrome P4502E1 in Patients with Alcoholism / 대한진단검사의학회지

BACKGROUND: The purpose of this study was to investigate genetic polymorphisms of cytochrome P4502E1 (CYP2E1) among healthy control and alcoholic Koreans in order to determine its relation-ship to the development of alcoholism. We also evaluate the diagnostic usefulness of carbohydrate deficient transferrin (CDT) in alcoholism. METHODS: The healthy control group included 72 males and 32 females. Patients with alcoholism included 53 males and 12 females who met DSM-IV diagnostic criteria (American Psychiatric Asso-ciation, 1994) and were admitted to alcoholism treatment units. Rsa I and Pst I restriction fragment length polymorphisms of CYP2E1 gene PCR product determined the genotype of CYP2E1. The serum level of CDT was analyzed by Behring Nephelometer II using %CDT turbidimetric immunoassay kit. RESULTS: The prevalence of CYP2E1 genotypes was 74.0% for type A, 23.1% for type B, and 2.9% for type C in the 104 healthy subjects, and 93.8% for type A and 6.2% for tyupe B in the 65 patients with alcoholism. The allele frequency of c1 and c2 of CYP2E1 was 85.6% and 14.4%, respectively, in the control group and 96.9% and 3.1%, respectively, in the alcoholics. The %CDT range in healthy controls and alcoholics was 0-7.8% and 3.1-21.1%, respectively. The serum CDT level in the patients with alcoholism (14.4 +/-4.5, mean +/-SD) was higher than that of healthy controls (3.2 +/-1.2, ) (P<0.05). The sensitivity, specificity, positive predictive value, negative predictive value, false positive rate, false negative rate, and test efficiency of %CDT were 85.1%, 93.3%, 88.7%, 90.6%, 6.7%, 15.4%, and 89.9%, respectively. CONCLUSIONS: There was a significant difference in frequencies of CYP2E1 genotype (P=0.001) and allele (P=0.003) between patient with alcoholism and control group, and the absence of CYP2E1 c2 allele was associated with alcoholism. Assessment of CDT yielded useful and objective informa-tion in the diagnosis and identification of alcoholism.

Induction of Hepatic Microsomal Cytochrome P450 by N,N-dimethylformamide in Sprague-Dawley Rats / 예방의학회지

OBJECTIVES: In order to gain a better understanding of the mechanism of DMF toxicity, recent studies have focused on hepatic drug metabolizing enzymes. In this study, we investigated the effects of DMF on the induction of P450 and the activities of other related enzymes in rat liver microsomes. METHODS: DMF was administered to male Sprague Daweley rats by intraperitoneal injection at 0(control), 450(D1), 900(D2), 1,800(D3) mg DMF/kg body weight in olive oil once a day for three days. Hepatic P450 was measured by method of Omura and Sato. We evaluated selective assays for the three drug metabolizing cytochrome P450 isoenzymes 1A1, 2B1 and 2E1. RESULTS: The content of microsomal protein, P450 and b5 were tended to be decreased in DMF treated group, but they were not statistically significant. The activity of NADPH-cytochrome P450 reductase was significantly increased dose dependently(p<0.01), but the activity of NADH-b5 reductase was decreased in the treated group(p<0.01). The activities of PROD and EROD were not significant between control and treated group. The activities of pNPH in the DMF treated groups were higher than that of the control group(p<0.01). When Western immunoblottings were carried out utilizing three monoclonal antibodies which were specific against P4501A1/1, P4502B1/2 and P4502E1, the strong density band corresponding to P4502E1 was observed with the microsomes obtained from the rats treated with DMF. But there were no significant increased in the P4501A1/2 and P4502B1/2 band densities in immunoblotting. CONCLUSIONS: These result suggested that P4502E1 was inducible by DMF and P4502E1 isozyme might be responsible for the hydroxylation of DMF to HMMF.