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1.
李烨  戴国炜  李燕  刘耕陶 《药学学报》2001,36(10):723-726
目的 研究双环醇对扑热息痛(对乙酰氨基酚)引起小鼠肝能量代谢紊乱和线粒体功能障碍的保护作用。方法 小鼠ip扑热息痛120mg·kg-1 引起急性肝损伤,观察血清谷丙转氨酶(ALT)和谷草转氨酶(AST)水平、肝活体磷谱、肝线粒体膜流动性及线粒体ATPase活性的改变。结果 双环醇可显著抑制扑热息痛中毒小鼠PME/ATP及PME/PDE的升高。双环醇(200mg·kg-1)可显著降低扑热息痛导致的线粒体膜流动性下降,并对线粒体ATPase活性降低有显著保护作用。结论 双环醇可保护扑热息痛导致的急性肝损伤,使肝脏能量代谢和磷脂代谢趋于正常,并对损伤的线粒体功能有显著的保护作用  相似文献   

2.
鲨肝活性肽对对乙酰氨基酚致小鼠急性肝损伤的保护作用   总被引:7,自引:0,他引:7  
目的探讨鲨肝活性肽(sHSS)对对乙酰氨基酚(AAP)致小鼠急性肝损伤的保护作用。方法用AAP(200 mg·kg-1,ip)诱导小鼠急性肝损伤,用改良赖氏法测血清ALT和AST,通过光镜和电镜观察肝细胞显微和亚显微结构的变化,用流式细胞仪分析肝细胞凋亡,同时用RT-PCR方法分析Fas mRNA表达水平。结果sHSS 3.0和1.5 mg·kg-1可显著降低肝损伤小鼠血清ALT和AST的水平;改善模型鼠肝组织细胞坏死及炎症反应;高剂量sHSS(3 mg·kg-1)对肝线粒体具有保护作用,下调Fas mRNA的表达水平,并具有抗凋亡作用。结论sHSS对AAP诱导的肝损伤具有明显的保护作用,其机制可能与保护肝线粒体、抑制Fas基因表达及肝细胞凋亡有关。  相似文献   

3.
青蒿琥酯对小鼠实验性肝损伤的保护作用   总被引:5,自引:1,他引:5  
研究抗疟新药青蒿琥酯(Art)对扑热息痛(AAP)和CCl_4引起的小鼠急性肝损伤的保护作用。实验结果证实,预先给小鼠ip Art200mg/kg,或100mg/kg共3次,其血清GPT和肝脏病变均明显低于对照组;并能降低AAP中毒小鼠的死亡率,对抗AAP所致小鼠早期肝糖元下降。此外,Art尚能显著缩短小鼠戊巴比妥钠睡眠时间,提示它可能具有诱导肝脏药物代谢酶作用。  相似文献   

4.
小花清风藤保肝作用实验研究   总被引:9,自引:0,他引:9  
刘易蓉  邱晓春  陈惠 《中国药房》2008,19(30):2341-2342
目的:研究小花清风藤(SPS)提取物对小鼠实验性肝损伤的保护作用。方法:采用四氯化碳(CCl4)、扑热息痛(AAP)复制小鼠肝损伤模型,测定小鼠血清谷丙转氨酶(ALT)、谷草转氨酶(AST)的活性。结果:小花清风藤提取物对2种肝损伤模型小鼠血清AST、ALT的活性有一定降低作用。结论:小花清风藤具有一定的保肝作用。  相似文献   

5.
中草药对肝损伤中肝细胞线粒体的保护机制   总被引:3,自引:2,他引:3  
毛德文  邱华  刘洁 《中国药房》2005,16(22):1745-1747
线粒体是细胞中最重要的细胞器,它对调控细胞凋亡及坏死起着重要作用.近年国内、外的研究表明,线粒体功能障碍是各种肝损伤(肝功能衰竭、肝纤维化、脂肪肝等)发生的重要机制之一.中草药因其具有疗效确切、副作用少、费用低等特点,在肝病的治疗中扮演着日益重要的角色,其通过保护线粒体功能干预肝损伤进程的机制亦越发明朗.本文就其研究进展加以综述,旨在为更深入、系统地探讨中草药抗肝损伤的研究提供可资借鉴的思路.  相似文献   

6.
清肝饮煎剂对对乙酰氨基酚所致肝损伤小鼠的保护   总被引:1,自引:0,他引:1  
向敏  王光莲  丁龙其 《医药导报》2004,23(4):0213-0214
目的:研究清肝饮煎剂(qingganying,QGY)对由对乙酰氨基酚(AAP) 所致肝损伤小鼠的保护作用。方法:采用AAP诱发小鼠肝损伤模型,观察小鼠血清丙氨酸氨基转移酶(ALT)、天门冬氨酸氨基转移酶(AST),总胆红素(SB)的变化,并做肝脏病理切片。结果:各剂量QGY可降低小鼠AST活性,中剂量(生药28 g·kg 1)、大剂量(生药56 g·kg 1)可降低ALT活性和SB含量。病理切片观察显示,AAP模型组肝细胞带状坏死,肝细胞呈弥漫性变化,QGY大剂量组肝小叶结构完整、清晰,少量细胞点状坏死,少量淋巴细胞浸润,病变程度与AAP模型组比较减轻。结论:QGY对AAP所致肝损伤小鼠有一定的保护作用。  相似文献   

7.
某些化学物致肝损伤机制的研究进展   总被引:5,自引:0,他引:5  
施畅  廖明阳 《毒理学杂志》2004,18(3):196-198
肝脏位于胃肠道与机体其他部位之间的战略重地,担负着机体许多重要功能,同时也是外源性化合物生物转化的主要器官,肝脏这种独特的血管布局和分泌、合成、代谢功能决定其为毒物作用的主要靶点。外源性化学物引起肝损伤的机制很复杂,目前对肝损伤机制尚无统一的分类标准。现就外源性化学物致胆汁淤积、细胞骨架破坏、线粒体损伤、活性氧或活性氮介导损伤、促炎症细胞介导等致肝损伤机制作一综述。  相似文献   

8.
近年国内外研究表明,线粒体功能异常是各种肝损伤(肝功能衰竭、肝硬化、脂肪肝等)发生的重要机制之一,而在药物性肝损伤发展过程中线粒体也起着重要作用。异烟肼是临床应用广泛、效果显著的抗结核药,但在治疗过程中常引起药物性肝损伤。在某种程度上妨碍了结核病的治疗。研究发现线粒体损伤是异烟肼肝损伤发生发展中关键一环,异烟肼及其毒性产物肼可通过激动氧化应激反应;抑制线粒体呼吸链中酶的活性;干扰细胞能量代谢及对线粒体膜产生攻击等方式使其功能异常,最终导致线粒体损伤,进而启动细胞凋亡程序。本文将对线粒体在异烟肼致药物性肝损伤中的作用进行综述,旨在从亚细胞水平解释异烟肼致肝毒性的机制,为阐明异烟肼的肝毒性提供更为有力的证据。  相似文献   

9.
线粒体是物质氧化和能量转换的场所,在能量代谢及自由基的产生、衰老、凋亡中起着重要作用。线粒体的呼吸链缺陷、代谢酶失活、结构改变、基因突变等因素都会影响整个细胞的正常功能,从而导致病变的发生。线粒体是药物毒性作用的重要靶标,肝脏作为药物代谢的重要脏器,也是药物引发损伤的主要靶器官。一些抗病毒药物、抗肿瘤药物和抗生素等可显著诱导肝脏线粒体损伤。药物主要通过改变线粒体结构、酶的活性或减少mtDNA的合成,进一步破坏β-脂质氧化和肝细胞的氧化能力,最终诱发肝损伤。综述药源性肝损伤领域有关线粒体损伤的研究进展,为预防和诊断药源性肝损提供思路。  相似文献   

10.
药物性肝损伤是临床常见的药源性疾病之一,也是药物临床试验失败和撤市的主要原因之一。三唑类抗真菌药物是治疗侵袭性真菌感染的主要药物,对多种临床常见真菌具有良好的抗菌活性,临床应用广泛。但随着三唑类抗真菌药物临床应用的日益增多,其肝损伤不良反应的报道也越来越多,给该类药物的临床应用带来一定挑战。三唑类抗真菌药物致肝损伤的影响因素包括药物浓度、年龄、基因多态性、炎症等,发生机制包括氧化应激、胆汁淤积、调节细胞色素P450的表达及脂质代谢异常等多个方面。本文将对三唑类抗真菌药物致肝损伤的临床特点、影响因素及发生机制的研究进展进行综述,以期为该类药物肝损伤的深入研究及临床安全合理应用提供参考。  相似文献   

11.
Neutrophils are recruited into the liver after acetaminophen (AAP) overdose but the pathophysiological relevance of this acute inflammatory response remains unclear. To address this question, we compared the time course of liver injury, hepatic neutrophil accumulation and inflammatory gene mRNA expression for up to 24 h after treatment with 300 mg/kg AAP in C3Heb/FeJ and C57BL/6 mice. Although there was no relevant difference in liver injury (assessed by the increase of plasma alanine aminotransferase activities and the areas of necrosis), the number of neutrophils and the expression of several pro-inflammatory genes (e.g., tumor necrosis factor-alpha, interleukin-1beta and macrophage inflammatory protein-2) was higher in C3Heb/FeJ than in C57BL/6 mice. In contrast, the expression of the anti-inflammatory genes interleukin-10 and heme oxygenase-1 was higher in C57BL/6 mice. Despite substantial hepatic neutrophil accumulation, none of the liver sections from both strains stained positive for hypochlorite-modified proteins, a specific marker for a neutrophil-induced oxidant stress. In addition, treatment with the NADPH oxidase inhibitors diphenyleneiodonium chloride or apocynin or the anti-neutrophil antibody Gr-1 did not protect against AAP hepatotoxicity. Furthermore, although intercellular adhesion molecule-1 (ICAM-1) was previously shown to be important for neutrophil extravasation and tissue injury in several models, ICAM-1-deficient mice were not protected against AAP-mediated liver injury. Together, these data do not support the hypothesis that neutrophils aggravate liver injury induced by AAP overdose.  相似文献   

12.
Acetaminophen (AAP) overdose can cause severe hepatotoxicity and even liver failure in experimental animals and humans. Despite substantial efforts over the last 30 years, the mechanism of AAP-induced liver cell injury is still not completely understood. It is widely accepted that the injury process is initiated by the metabolism of AAP to a reactive metabolite, which first depletes glutathione and then binds to cellular proteins including a number of mitochondrial proteins. One consequence of this process may be the observed inhibition of mitochondrial respiration, ATP depletion and mitochondrial oxidant stress. In the presence of sufficient vitamin E, reactive oxygen formation does not induce severe lipid peroxidation but the superoxide reacts with nitric oxide to form peroxynitrite, a powerful oxidant and nitrating agent. Peroxynitrite can modify cellular macromolecules and may aggravate mitochondrial dysfunction and ATP depletion leading to cellular oncotic necrosis in hepatocytes and sinusoidal endothelial cells. Thus, we hypothesize that reactive metabolite formation and protein binding initiate the injury process, which may be then propagated and amplified by mitochondrial dysfunction and peroxynitrite formation. This concept also reconciles many of the controversial findings of the past and provides a viable hypothesis for the mechanism of hepatocellular injury after AAP overdose.  相似文献   

13.
DNA fragmentation in hepatocytes occurs early after acetaminophen (AAP) overdose in mice. DNA strandbreaks can induce excessive activation of poly(ADP-ribose) polymerases (PARP), which may lead to oncotic necrosis. Based on controversial findings with chemical PARP inhibitors, the role of PARP-1 activation in AAP hepatotoxicity remains unclear. To investigate PARP-1 activation and evaluate a pathophysiological role of PARP-1, we used both PARP inhibitors (3-aminobenzamide; 5-aminoisoquinolinone) and PARP gene knockout mice (PARP-/-). Treatment of C3Heb/FeJ mice with 300 mg/kg AAP resulted in DNA fragmentation and alanine aminotransferase (ALT) release as early as 3 h, with further increase of these parameters up to 12 h. Few nuclei of hepatocytes stained positive for poly-ADP-ribosylated nuclear proteins (PAR) as indicator for PARP-1 activation at 4.5 h. However, the number of PAR-positive cells and staining intensity increased substantially at 6 and 12 h. Pretreatment with 500 mg/kg 3-aminobenzamide before AAP attenuated hepatic glutathione depletion and completely eliminated DNA fragmentation and liver injury. Delayed treatment several hours after AAP was still partially protective. On the other hand, liver injury was not attenuated in PARP-/- mice compared to wild-type animals. Similarly, the specific PARP-1 inhibitor 5-aminoisoquinolinone (5 mg/kg) was not protective. However, 3-aminobenzamide attenuated liver injury in WT and PARP-/- mice. In summary, PARP-1 activation is a consequence of DNA fragmentation after AAP overdose. However, PARP-1 activation is not a relevant event for AAP-induced oncotic necrosis. The protection of 3-aminobenzamide against AAP-induced liver injury was due to reduced metabolic activation and potentially its antioxidant effect but independent of PARP-1 inhibition.  相似文献   

14.
Previously, we demonstrated that oltipraz [OTP: 5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione] prevented the hepatotoxicity of acetaminophen (AAP) in hamsters and that the observed protection was not related to increases in hepatic reduced glutathione (GSH) levels. These experiments were designed to elucidate the mechanism of OTP-induced protection with respect to an apparent non-GSH-dependent system. Marked differences in the relative amounts of hepatic GSH content depleted by AAP in control vs OTP-treated hamsters occurred. Urinary recoveries of AAP and metabolites indicated that more AAP-glucuronide was formed at the expense of other major metabolites (AAP-GSH, -N-acetylcysteine, and -sulfate) in OTP-treated hamsters, while plasma toxicokinetic modeling suggested a greater rate of AAP systemic clearance. An increased apparent formation rate constant for AAP glucuronidation (135%), in concert with significantly lower apparent formation rate constants for those metabolites which reflect the production of the reactive intermediate from AAP (glutathione and N-acetylcysteine), provide the rationale for this shift of metabolism. The biochemical basis for metabolic shunting is significantly elevated hepatic UDP-glucuronic acid content, an increased calculated UDP-glucuronic acid synthetic rate, and an increased liver microsomal UDP-glucuronyl transferase activity in OTP-treated animals. These changes in AAP conjugation were concomitant with decreased fractional clearance of AAP via bioactivation and less in vivo AAP covalent binding. These data support the hypothesis that OTP provides a protecting effect from AAP hepatotoxicity due to an augmented and predisposing glucuronidation capacity.  相似文献   

15.
The role of apoptosis in acetaminophen (AAP)-induced hepatic injury was investigated. Six hours after AAP administration to BALB/c mice, a significant loss of hepatic mitochondrial cytochrome c was observed that was similar in extent to the loss observed after in vivo activation of CD95 by antibody treatment. AAP-induced loss of mitochondrial cytochrome c coincided with the appearance in the cytosol of a fragment corresponding to truncated Bid (tBid). At the same time, tBid became detectable in the mitochondrial fraction, and concomitantly, Bax was found translocated to mitochondria. However, AAP failed to activate the execution caspases 3 and 7 as evidenced by a lack of procaspase processing and the absence of an increase in caspase-3-like activity. In contrast, the administration of the pan-inhibitor of caspases, benzyloxycarbonyl-Val-Ala-DL-Asp-fluoromethylketone (but not its analogue benzyloxycarbonyl-Phe-Ala-fluoromethylketone) prevented the development of liver injury by AAP and the appearance of apoptotic parenchymal cells. This correlated with the inhibition of the processing of Bid to tBid. The caspase inhibitor failed to prevent both the redistribution of Bax to the mitochondria and the loss of cytochrome c. In conclusion, apoptosis is an important causal event in the initiation of the hepatic injury inflicted by AAP. However, as suggested by the lack of activation of the main execution caspases, apoptosis is not properly executed and degenerates into necrosis.  相似文献   

16.
枸杞对实验性肝损伤的保护作用   总被引:10,自引:0,他引:10  
目的探讨枸杞对实验性肝损伤的保护作用。方法用四氧化碳(CCl4)建立小鼠、大鼠肝损伤模型。给小鼠口服枸杞水煎剂3.75、7.5g/kg,大鼠口服枸杞水煎剂2.86、5.72g/kg,以赖氏法测定小鼠、大鼠血清丙氨酸转氨酶(ALT)活性,甲醇法测定大鼠血清胆红素含量,并观察醋氨酚对小鼠的影响。结果枸杞水煎剂能有效地降低CCl4引起的小鼠ALT升高,使醋氨酚中毒的小鼠生存率达80%,大鼠血清ALT活力与胆红素含量亦显著下降。结论枸杞具有抗CCl4所致的动物肝细胞损伤作用,本实验为枸杞在临床上治疗肝炎、脂肪肝提供了一定的实验依据。  相似文献   

17.
Mitochondrial oxidant stress and peroxynitrite formation have been implicated in the pathophysiology of acetaminophen-induced (AAP-induced) liver injury. Therefore, we tested the hypothesis that lipid peroxidation (LPO) might be involved in the injury mechanism. Male C3Heb/FeJ mice fed a diet high in vitamin E (1 g d-alpha-tocopheryl acetate/kg diet) for 1 week had 6.7-fold higher hepatic tocopherol levels than animals on the control diet (8.2 +/- 0.1 nmol/g liver). Treatment of fasted mice with 300 mg/kg AAP caused centrilobular necrosis with high plasma alanine aminotransferase (ALT) activities at 6 h (3280 +/- 570 U/l) but no evidence of LPO (hepatic malondialdehyde, 4-hydroxynonenal). Animals on the vitamin E diet had similar injury and LPO as mice on the control diet. To verify a potential effect of the vitamin E diet on drug-induced liver injury, animals were pretreated with a combination of phorone, FeSO4, and allyl alcohol. We observed, 2 h after allyl alcohol, massive LPO and liver cell injury in the livers of animals on the control diet, as indicated by a 32-fold increase in malondialdehyde levels, extensive staining for 4-hydroxynonenal, and ALT activities of 2310 +/- 340 U/l. Animals on the vitamin E diet had 40% lower hepatic malondialdehyde levels and 85% lower ALT values. Similar results were obtained when animals were treated for 3 days with alpha- or gamma-tocopherol (0.19 mmol/kg, ip). Both treatments reduced LPO and injury after allyl alcohol but had no effect on AAP hepatotoxicity. Thus, despite the previously shown mitochondrial oxidant stress and peroxynitrite formation, LPO does not appear to be a critical event in AAP-induced hepatotoxicity.  相似文献   

18.
王慧  陈真 《安徽医药》2011,15(7):799-801
肝纤维化(HF)是多种致病因素作用于肝细胞引起肝细胞变性坏死后的共同病理基础,肝纤维化是肝硬化形成的早期阶段和必经阶段,是一可逆过程,但若病因持续存在发展为肝硬化则为不可逆的.其本质是细胞外基质(ECM)在肝脏过度沉积,而肝星状细胞(HSC)是大多数ECM的细胞来源,因此该文对与HSC活化增殖密切相关的TGF及PDGF...  相似文献   

19.
These studies were designed to test the hypothesis that oltipraz (OTP) provided protection against AAP intoxication in a sensitive species, the hamster; and further, to show that the sparing effect was related to the marked increase in hepatic reduced glutathione (GSH) levels. Dose-response and time-course experiments demonstrated that maximal increases in liver GSH occurred at 48 hr after an oltipraz dose of approximately 2.0 mmol/kg (po). Accompanying greater GSH levels were increased glutathione disulfide (GSSG) levels. Decreased indices of the oxidation state of glutathione and of hepatic pyridine nucleotides indicated a greater share of glutathione existed as GSH and that increased reducing equivalents were present, respectively. Additionally, glutathione disulfide reductase activity was greater in OTP-treated groups. Glutathione S-transferase activities were only marginally increased. OTP treatment did not elicit observable hepatotoxicity, whereas AAP (2.6 mmol/kg, ip) resulted in a reproducible model of liver damage. OTP-treated groups were protected from AAP-induced toxicity, as shown by decreased plasma appearance of liver enzymes and unremarkable histopathology. However, the degree of liver GSH depletion by AAP was fourfold greater in non-OTP treated groups compared to those which had received the dithiolthione. To test the importance of increased hepatic GSH, the biosynthesis of glutathione was interrupted. Buthionine sulfoximine (BSO) treatment decreased hepatic GSH, the biosynthesis of glutathione was interrupted. Buthionine sulfoximine (BSO) treatment decreased hepatic GSH content to 50% of control in hamsters which either had or had not received OTP. The groups receiving BSO and AAP incurred 83% lethality, while no lethality, unremarkable liver histopathology, and plasma enzyme levels consistent with control were found in the group receiving OTP, BSO, and AAP. Treatment with BSO only had no influence on hepatotoxicity parameters. These results indicate that the increased GSH levels in the OTP-treated hamster are coincidental to the sparing effect of OTP and are not central to the protection scheme in AAP-induced hepatotoxicity.  相似文献   

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