美他多辛对酒精性脂肪肝大鼠CYP2E1表达的影响及其预防作用

目的探讨美他多辛对酒精性脂肪肝大鼠肝组织中CYP2E1表达的影响及其治疗酒精性脂肪肝的机制。方法 30只清洁级Wistar大鼠随机分为3组:正常组、模型组和预防组。采用乙醇(8g·kg~(-1)·d~(-1))灌胃,每日2次,间隔8h,持续8wk,建立酒精性脂肪肝动物模型。正常组:不灌服乙醇,给予等体积生理盐水;模型组:在每次灌服乙醇1h后,给予等体积灭菌注射用水;预防组:在每次灌服乙醇1h后给予美他多辛(300mg·kg~(-1)·d~(-1))。8 wk灌胃结束后,B超、HE染色和油红O染色观察脂肪肝形态变化,采用自动生化仪检测血清丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)、三酰甘油(TG)、总胆固醇(TC)含量,免疫组化和蛋白印迹法检测大鼠肝组织中CYP2E1的表达。结果模型组ALT、AST、TG、TC含量明显升高,与正常组和预防组比较有显著差异(P<0.01,P<0.05),预防组明显降低CYP2E1表达与模型组比较有显著差异(P<0.01)。结论美他多辛通过抑制CYP2E1表达的上调,有效预防酒精性脂肪肝的发展。     

美他多辛联合硫普罗宁治疗酒精性脂肪肝疗效观察

我院于2011年4月-2012年3月应用美他多辛联合硫普罗宁治疗酒精性脂肪肝患者50例,取得了满意疗效。1资料与方法1.1临床资料50例患者均为男性,平均年龄(50.1±5.2)岁,均伴有转氨酶升高,均有>5年的饮酒史,日饮酒精量>40g,均除外病毒、药物、寄生虫及代谢异常等引起的脂肪肝。     

二陈汤对非酒精性脂肪肝CYP2E1及线粒体能量代谢的影响

摘 要 目的：观察二陈汤对非酒精性脂肪肝模型小鼠肝细胞色素酶CYP2E1及线粒体能量代谢的影响,探讨二陈汤中君臣两药法半夏及陈皮在非酒精性脂肪肝治疗中的作用。方法: 分别灌胃给予非酒精性脂肪肝动物模型：二陈汤及分别去除法半夏,陈皮后的二陈汤,检测小鼠血清谷氨酸转氨酶（ALT）、天门冬氨酸氨基转移酶（AST）,血浆三酰甘油（TG）、总胆固醇（TC）,肝脏超氧化物歧化酶（SOD）及丙二醛(MDA)水平,同时检测小鼠肝组织CYP2E1含量及三磷酸腺苷（ATP）含量。结果: 脂肪肝小鼠模型CYP2E1含量明显升高,线粒体能量代谢异常。与模型组相比,二陈汤可显著改善模型鼠ALT、AST、TG、TC、SOD及MDA水平,降低CYP2E1含量,恢复肝组织能量代谢。二陈汤去除法半夏后,改善体内ALT、AST、TC水平作用,及恢复肝组织线粒体能量代谢能力均显著下降（P<0.05）;二陈汤去除陈皮后,改善体内ALT、AST、TC、SOD、MDA水平的作用,以及对CYP2E1含量抑制作用则明显降低（P<0.05）。结论:二陈汤有效改善非酒精性脂肪肝病变,并可有效降低非酒精性脂肪肝小鼠肝组织CYP2E1含量,恢复其线粒体能量代谢,而法半夏与陈皮发挥协同增效作用。     

美他多辛治疗酒精性肝病

目的旨在观察美他多辛治疗酒精性肝病的临床疗效和安全性。方法采取随机、双盲安慰剂平行对照试验,其中安慰剂组为空白对照药,研究组为美他多辛,疗程为6周。结果及结论美他多辛治疗酒精性肝病6周其生化疗效的显效率、有效率分别为68.18%和27.27%,总有效率为95.45%,而空白对照组其生化疗效的显效率、有效率分别为9.09%和45.45%,总有效率为54.55%。两组相比有显著性差异(P<0.05)。本中心研究中,试验组共有2例发生不良反应,表现为腹泻,均为轻度,不良反应发生率为9.09%;对照组亦有1例发生不良反应,表现为头晕,均为轻度,不良反应发生率为4.55%。两组比较无显著差异(P>0.05)。     

美他多辛对雄性大鼠的生殖毒性

美他多辛 (Metadoxine ,MTDX)是意大利 80年代上市的一种代谢平衡药 ,它能减轻乙醇戒断综合征及早期标志物氨的排除 ,是目前临床用于治疗化学性和乙醇性肝病的药物[1 3 ] 。MTDX化学名称为吡哆素L 2 吡咯烷酮 5 羧酸酯 ,吡哆素是维生素B6由吡哆醇 (PN)、吡哆醛 (PL)和吡哆胺组成 ,L 2 吡咯烷酮 5 羧酸酯俗称L 焦谷氨酸 (L 2 Pyrrolidone 5 carboxylate ,L PCA) ,MTDX由二者 1∶1聚合而成 ,是 1对离子 ,在体内又分解成这 2种离子。目前 ,国内外对于MTDX的报道仅见于其药效机制方面 ,未见其对雄性生殖系统毒性作用及其机…     

复方银杏叶胶囊对肝损伤大鼠CYP2E1、CYP3A4的影响

目的研究复方银杏叶胶囊(CGB)对酒精性肝损伤大鼠CYP2E1、CYP3A4活性的影响。方法正常组和酒精性肝损伤模型组均以CGB[(250 mg/(kg.d)]灌胃,分别在灌胃CGB前及灌胃1周后,灌胃探针药氯唑沙宗(50 mg/kg)及氨苯砜(20 mg/kg),于探针药灌后24 h内不同时间点采血,测定各探针药血药浓度。结果灌胃CGB前,模型组氯唑沙宗和氨苯砜的AUC0-24、Cmax均显著低于正常组(P<0.05或P<0.01)。灌胃CGB后,模型组氯唑沙宗和氨苯砜的AUC0-24、Cmax均较灌胃前显著升高(P<0.05或P<0.01);且氯唑沙宗的t1/2灌胃CGB后明显高于灌胃前(P<0.05)。结论 CGB能够明显抑制酒精性肝损伤大鼠CYP2E1、CYP3A4酶活性。     

治疗酒精性肝病新药——欣立得(美他多辛胶囊)

美他多辛是一种新型的治疗酒精性肝病的药物，它是由吡哆辛和吡咯烷酮组成的离子化合物，为乙醛脱氢酶激活荆，可通过加速体内乙醇和乙醛的代谢及排泄，降低酒精对组织的损害，增加中枢神经系统释放GABA和乙酰胆碱，改善酒精引起的抑制和兴奋症状；对抗乙醇中毒引起的ATP下降和细胞谷胱甘肽水平降低，从而调节机体代谢平衡，有效预防和治疗急、慢性酒精中毒引起的神经和肝脏损害。在已有的临床研究和应用中，美他多辛可有效预防和治疗急、慢性酒精引起的神经和肝脏损害，其安全性高，未发现用药时有严重的不良反应发生的报道，因此美他多辛可作为治疗急、慢性酒精中毒性疾病的一线用药。     

美他多辛联合硫普罗宁治疗酒精性肝病的疗效观察

目的:观察美他多辛联合硫普罗宁治疗酒精性肝病的临床疗效。方法:回顾性选取山西省人民医院和太原市第三人民医院2013年10月-2015年12月就诊的70例酒精性肝病患者资料,按照治疗方案分为治疗组和对照组,各35例。对照组患者在基础治疗方案上给予硫普罗宁肠溶片0.2 g,po,tid;治疗组患者在对照组基础上给予美他多辛片1.0 g,po,bid。两组患者疗程均为6周。观察两组患者治疗前后丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)、γ-谷氨酰转肽酶(γ-GT)、总胆红素(TBIL)、总胆固醇(TC)、三酰甘油(TG)和清蛋白球蛋白比值(A/G)等指标水平,血清Ⅳ型胶原(Ⅳ-C)、透明质酸(HA)和层黏连蛋白(Ln)等肝纤维指标水平,门静脉(MPV)、脾静脉(SPV)直径和脾厚以及临床疗效,并记录不良反应发生情况。结果:两组患者血清ALT、AST、γ-GT、TBIL、TC、TG水平均明显下降,A/G水平明显上升,且治疗组患者上述指标变化较对照组更为显著,差异均有统计学意义(P<0.05);治疗组患者血清Ⅳ-C、HA、Ln、MPV、SPV和脾厚等均明显下降/减小,且明显低于对照组,差异均有统计学意义(P<0.05)。治疗组患者总有效率(94.29%)明显高于对照组(62.86%),差异有统计学意义(P<0.05)。两组患者治疗过程中均未见明显不良反应发生。结论:美他多辛联合硫普罗宁治疗酒精性肝病疗效较好,且安全性高。     

山楂对正常大鼠肝脏CYP2E1活性的影响

目的:探讨山楂对大鼠肝脏CYP2E1活性的影响,为山楂的药食同源应用提供依据.方法:实验分为正常对照组、山楂高剂量组和山楂低剂量组,给予山楂水提取液14天后,抽取肝微粒体酶,利用高效液相色谱检测CYP2E1代谢低物的能力.结果:山楂高剂量和低剂量组均能显著抑制CYP2E1的活性.结论:山楂是一种良好的药食同源的中药,能通过抑制CYP2E1活性对机体起保护作用.     

Adenovirus-mediated expression of CYP2E1 produces liver toxicity in mice.

Induction of cytochrome P450 2E1 by ethanol is believed to be one of the central pathways by which ethanol generates a state of oxidative stress and causes hepatotoxicity. In order to evaluate the biochemical and toxicological actions of CYP2E1 and its sensitization of hepatotoxin-induced injury, an adenovirus which can mediate overexpression of CYP2E1 was constructed. Injecting this virus into mice through the tail vein elevated CYP2E1 protein and activity twofold in the liver of the mice compared with the mice injected with Ad-LacZ or saline. Transaminase levels were dramatically increased in mice injected with the CYP2E1 adenovirus. Histological evaluation of liver specimens of mice injected with Ad-2E1 showed liver cell injury. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay demonstrated that more cells were stained positively in the liver of the mice infected with Ad-2E1 than in the liver of the mice infected with Ad-LacZ. 3-Nitrotyrosine protein adducts and protein carbonyl adducts were increased in the liver of the mice infected with Ad-2E1 compared with Ad-LacZ. This potentiated toxicity most likely reflects interactions between CYP2E1- and adenovirus-mediated toxicity pathways. These results show that adenovirus-mediated overexpression of CYP2E1 could induce liver toxicity in mice and suggests a mechanism involving oxidative/nitrosative stress.     

淫羊藿苷对小鼠肝微粒体细胞色素P450酶及其亚型CYP2E1活性的影响

目的 研究淫羊藿苷对小鼠肝脏微粒体细胞色素P450(CYP)总酶含量及其亚型CYP2E1、CYP3A和CYP1A1活性的影响.方法 给予小鼠ig淫羊藿苷(50、100、200 mg·kg-1·d-1),3d后钙沉淀法制备肝细胞微粒体,UV法测定肝微粒体CYP的含量及其亚型CYP2E1与CYP3A的活性;荧光分光光度法测定肝微粒体CYP1A1的活性.结果 高剂量淫羊藿苷可降低小鼠肝脏微粒体CYP的含量(约54%)、抑制CYP2E1的活性(抑制率为53.1%),对CYP3A和CYP1A1的活性无影响.结论 大剂量淫羊藿苷可降低小鼠肝脏微粒体CYP的总含量,并抑制其亚型CYP2E1的活性.     

CYP2 E1在酒精性肝病中的作用

酒精性肝病(ALD)是一种长期大量饮酒所致的慢性肝脏疾病。乙醇经肝脏代谢产生大量的自由基和活性氧。氧化应激在乙醇引起肝损伤的机制发挥关键作用。在肝脏,细胞色素P450 2E1(CYP2E1)可被乙醇诱导并参与乙醇代谢,CYP2E1是一种有效的活性氧产生酶,产生超氧阴离子自由基和过氧化氢,铁催化剂的存在下,产生羟基自由基。该文主要总结了CYP2E1在ALD发病过程中的作用及机制,为ALD的临床治疗提供思路。     

酒精性肝损伤大鼠细胞色素P450 CYP2E1和细胞色素P450 CYP3A的代谢活性

目的观察酒精性肝损伤对大鼠细胞色素P450CYP3A(CYP3A)和细胞色素P450CYP2E1(CYP2E1)代谢活性的影响。方法采用ig给予白酒制备大鼠酒精性肝损伤模型,检测血清中谷丙转氨酶(GPT)和谷草转氨酶(GOT)活性,采用HE染色法光镜下观测酒精对肝脏损伤程度。大鼠ip给予CYP3A探针药物咪达唑仑10mg·kg-1或ig给予CYP2E1探针药物氯唑沙宗50mg·kg-1后,采用高效液相色谱法测定不同时间点大鼠血浆中咪达唑仑和氯唑沙宗的血药浓度,并应用3P87软件计算其药代动力学参数,以考察CYP2E1和CYP3A的代谢活性的变化。大鼠ig给予氯唑沙宗80mg·kg-1后,热板方法测定大鼠添足次数和添足反射潜伏期。结果酒精性肝损伤可致大鼠肝小叶结构不清,肝索排列紊乱,肝细胞体积增大,呈弥漫性中度水变性,肝窦受压,大部分肝细胞胞浆内见大小不等的脂肪空泡;与正常对照组相比,酒精性肝损伤组大鼠GPT和GOT活性分别增加了16.0%和20.0%(P<0.05,P<0.01)。酒精性肝损伤致大鼠CYP2E1对探针药物氯唑沙宗的代谢活性增强,AUC,t1/2和cmax分别降低了38.0%,30.5%和35.0%(P<0.05);酒精肝损伤组大鼠氯唑沙宗镇痛效果明显降低;酒精性肝损伤致大鼠CYP3A对探针药物咪达唑仑的代谢活性增强,AUC,t1/2和cmax分别降低了122.6%,54.9%和56.9%(P<0.01,P<0.05)。结论酒精性肝损伤可使大鼠CYP2E1和CYP3A代谢活性增强。     

免疫性肝损伤和酒精性肝损伤中CYP2E1代谢活力的差异性变化

目的:观察免疫性肝损伤和酒精性肝损伤对大鼠CYP2E1代谢活力的影响。方法:采用尾静脉注射卡介苗诱发大鼠产生免疫性肝损伤,采用白酒灌胃法制备大鼠酒精性肝损伤模型,HPLC法测定经CYP2E1代谢的探针药物氯唑沙宗血药浓度经时变化。结果:卡介苗刺激可致大鼠肝脏明显肿大,大量单核、淋巴细胞浸润,肉芽肿形成;致大鼠CYP2E1对探针药物氯唑沙宗的代谢活性减弱,AUC增大,Cmax增大。酒精性肝损伤可致肝小叶结构不清,肝索排列紊乱,肝细胞体积增大,呈弥漫性中度水变性,肝窦受压,大部分肝细胞胞浆内见大小不等的脂肪空泡。致大鼠CYP2E1对探针药物氯唑沙宗的代谢活性增强,AUC减少,Cmax减少。结论:免疫性肝损伤可致CYP2E1代谢活性降低,酒精性肝损伤可致CYP2E1代谢活性增强。     

慢性间断性低氧对大鼠肝脏CYP3A_2和CYP2E_1的影响研究

目的研究慢性间断性低氧对大鼠肝脏CYP3A2和CYP2E1的影响。方法将大鼠随机分为对照组、低氧3d组、低氧7d组、低氧14d组、低氧28d组,低氧处理结束24h后,常规腹腔注射麻醉,摘取眼球血液2ml制备血清,并测定丙氨酸氨基转移酶(ALT)、天门冬酸氨基转移酶(AST)、红霉素N-脱甲基酶(ERD)、苯胺羟化酶(ANH)活性;取新鲜肝组织以制备微粒体和提取核糖核酸(RNA),并以RT-PCR进行基因片段扩增以检测大鼠肝脏细胞色素CYP3A2、CYP2E1的mRNA表达水平。结果慢性间断性低氧对血清ALT、AST活性无明显影响;低氧7d后,大鼠肝脏ERD、ANH活性明显升高,28d时诱导率分别为155.5%、42.2%;同时,CYP3A2、CYP2E1mRNA的表达水平也分别增加了220.5%、102.8%。结论慢性间断性低氧能显著增加大鼠肝脏ERD、ANH活性,其机制可能与其在转录水平上提高肝脏CYP3A2和CYP2E1的基因表达水平有关。     

Undernutrition during hyperoxic exposure induces CYP2E1 in rat liver

Induction of cytochrome P450 2E1 (CYP2E1) has been shown to occur through two distinct mechanisms. The first is seen by treatment of rats with acetone, pyrazole, and 4-methyl-pyrazole, which induces CYP2E1 protein without affecting the mRNA level. The second is observed in starvation, diabetes, and obesity, in which an increase of CYP2E1 protein is associated with an increase of the CYP2E1 mRNA. It has been reported by (Tindberg and Ingelman-Sundberg 1989) that hyperoxic exposure (95% O₂) induced a several-fold increase of CYP2E1 protein in both the liver and lung of exposed rats without affecting the level of CYP2E1 mRNA. During the course of our previous study which demonstrated hyperoxia-induced specific pretranslational induction of CYP1A1/2 in the liver and CYP1A1 in the lung, we observed a progressive increase of hepatic CYP2E1 mRNA in animals of the hyperoxia group. Hyperoxia is accompanied by some degree of starvation and our earlier experiments were conducted with rats of significantly greater body weight than those used by Tindberg and Ingelman-Sundberg (260 vs 150 g). Thus we reevaluated the changes of CYP2E1 in the current study with the use of food-restricted control, and by utilizing rats of comparable weight (∼150 g) to that utilized by Tindberg and Ingelman-Sundberg. The results obtained in the present study showed that there was a significant increase in the levels of hepatic CYP2E1 mRNA, protein, and p-nitrophenol hydroxylase activity in the food-restricted control group compared to the untreated controls. Rats from the hyperoxia group also demonstrated a similar increase of these three parameters in their livers but showed no significant difference compared with the results of the food-restricted control group. Rats weighing ∼260 g were also examined with similar food restriction and hyperoxia, and the results were essentially similar to those obtained with the younger rats. The lungs of rats from food-restricted control and hyperoxia groups showed no increase of any of the CYP2E1 parameters. The results obtained in the current study, therefore, indicate that hyperoxia has no effect on CYP2E1 expression in both the liver and lung. Increased CYP2E1 mRNA, protein, and p-nitrophenol hydroxylase activity seen in the liver of rats, but not in the lungs, are consistent with the notion that undernutrition during hyperoxia is the underlying mechanism for this induction. Received: 29 April 1997 / Accepted: 11 June 1997