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1.
用亚硝基铁氰化钠(SNP)作为NO生成前体,以0,1,2,4和8mg·kg-1ip给予大鼠,每日一次,连续5d,来研究外源性NO对大鼠肝脏细胞色素P450,苯胺羟化酶(AH),谷胱甘肽S-转移酶(GST)等药物代谢酶和过氧化氢酶(Cat),谷胱甘肽过氧化物酶(GSH-Px),超氧化物歧化酶(SOD)等抗氧化物酶活性以及脂质过氧化的体内影响情况.结果表明外源性NO能明显降低大鼠肝脏SOD,Cat,AH的活性和细胞色素P450的含量(P<0.05),并且高剂量组还能明显促进脂质过氧化发生(P<0.05),但对GSH-Px和GST的活性则无明显影响  相似文献   

2.
硒多糖、亚砷酸钠对大鼠肝微粒体酶和GSH-Px等的影响   总被引:1,自引:0,他引:1  
研究了硒多糖、亚砷酸钠在体内、外对大鼠肝微粒体酶细胞色素P-450、b5、NAD(P)H-细胞色素C还原酶、谷胱甘肽硫转移酶(GST)的影响;并通过测定硒多糖、亚砷酸钠对肝谷胱甘肽过氧化物酶(GSH-Px)和脂质过氧化(LPO)的影响,探讨了硒、砷相互作用的机理。结果表明:连续7天腹腔注射0.2mg/kg硒多糖,细胞色素P-450、b5的含量、GST的活性降低(P<0.05);硒多糖明显诱导GSH-Px的活性,降低脂质过氧化,拮抗亚砷酸钠对LPO的作用。亚砷酸钠显著增强肝细胞脂质过氧化(P<0.05),对GSH-Px和肝微粒体酶无明显影响  相似文献   

3.
为进一步探明肺心病时自由基代谢变化的规律,寻求肺心病治疗的新方案,以30例健康人作对照,对29例肺心病人的超氧化物歧化酶(SOD)总量(T-SOD)、锰SOD(Mn-SOD)活力、还原型谷胱甘肽(GSH)、丙二醛(MDA)过氧化氢酶(CAT)和总抗氧化能力(T-ACO)等八项自由基指标进行了检测,结果肺心病时T-SOD、Mn-SOD、铜锌SOD(CuZn-SOD)、CAT、GSH五项指标均显著低于正常对照组(P<0.01),肺心病急性期Mn-SOD和GSH显著低于缓解期(P<0.05),而T-ACO及MDA则高于正常人(P<0.01或P<0.05),Mn-SOD/T-SOD之比在肺心病时也有所升高但无统计学差异,MDA在急性期的增高程度与缓解期无显著差别(P>0.05)。初步认为肺心病患者的自由基代谢变化。主要表现为自由基的形成与清除失衡,应用抗氧化剂是治疗过程中的一项有效措施。  相似文献   

4.
L-2-氧-4-噻唑烷酸(L-OTC)是细胞内L-半胱氨酸的一个优良前体药,也是合成谷胱甘肽(GSH)的有效刺激剂,对机体无毒性[1]。Wiliamson等报道,L-OTC可使正常小鼠肝组织的GSH水平明显升高,可使对-乙酰氨基酚(P-AP)中毒小鼠...  相似文献   

5.
丹皮总甙对化学性肝损伤保护作用机制   总被引:5,自引:0,他引:5  
目的 研究丹皮总苷(TGM)对CCl4和D-Gal-N致小鼠化学性肝损伤的保护作用机制。方法 采用CCl4和D-Gal-N所致小鼠化学性肝损伤模型进行研究,用TBA法和DTNB法测定MDA和GSH-Px。结果 TGM具有促进肝脏糖原合成和提高血清蛋白含量的作用(P〈0.01),可明显降低肝匀浆脂质过氧化产物丙二醛(MDA)的含量(P〈0.01)及提高血清和肝脏谷胱甘肽过氧化物酶活力(P〈0.01)  相似文献   

6.
褪黑素抗自由基作用及其机制   总被引:16,自引:1,他引:16  
目的研究褪黑素(MEL)的抗自由基作用,并探讨其作用机制。方法以丙二醛(MDA)为指标,考察MEL对四氯化碳(CCl4)或氰化钾(KCN)处理小鼠肝或脑组织脂质的保护作用;考察MEL对环磷酰胺所致小鼠骨髓细胞微核的影响;观察MEL清除羟自由基(·OH)作用,及对醋氨酚处理小鼠肝谷胱甘肽(GSH)含量和大鼠红细胞超氧化物歧化酶(SOD)、过氧化氢酶(CAT)和全血谷胱甘肽过氧化物酶(GSH-Px)的影响。结果MEL(2.0,10.0mg·kg-1,ip)能显著对抗CCl4或KCN所致小鼠肝脏或脑组织丙二醛含量的增加。MEL(10.0mg·kg-1,ip)可明显抑制环磷酰胺引起的小鼠骨髓细胞微核增多。MEL(0.078~5.0mmol·L-1)可直接清除·OH。MEL(1.0,10.0mg·kg-1,ip)可显著对抗醋氨酚(AAP)所致小鼠GSH的耗竭作用。MEL(1.0,5.0mg·kg-1,ip)亦可显著提高大鼠红细胞内SOD、CAT、全血GSH-Px活性。结论MEL可保护脂质和核酸免受过氧化损伤,这可能与其直接清除·OH,提高机体GSH含量及增强SOD、CAT、GSH-Px活力有关。  相似文献   

7.
目的研究小鼠醋氨酚(Ace)的有关药代动力学及苯巴比妥钠(Phe)对其的影响。方法给正常小鼠和Phe50mg·kg-1ip7d的小鼠,尾静脉注射Ace100mg·kg-1,用HPLC法测定血浆Ace及尿液Ace、葡萄糖醛酸—Ace(GA)和硫酸—Ace(SA)含量,计算机自动曲线拟合,计算比较其有关药代动力学参数及尿液代谢产物累积排泄量。结果小鼠Ace血浆浓度量-时关系曲线呈一房室模型,T12为13.9±0.55min,CL为(0.04032±0.00382)L·kg-1·min-1,9h尿液Ace、GA和SA总累积排泄量为给药量的54.0%±6.21%。经Phe诱导后,AceT12缩短27.7%,CL增加25.2%,尿液GA减少19.3%(P<0.05)。结论至少在ICR和昆明种小鼠,Ace除与葡萄糖醛酸和硫酸结合外,还有其它重要代谢途径。Phe预处理明显加快小鼠血浆Ace消除,但该作用与葡萄糖醛酸和硫酸结合代谢反应无关。  相似文献   

8.
研究有氧运动及其合用人参茎叶皂苷(Gin)对饮食性高脂血症小鼠脂质代谢的影响。方法:通过喂养高胆固醇饲料20天建立高脂血症模型,以无负重游泳作为有氧运动方式,观察有氧运动及其合用Gin时对高脂状态下小鼠的影响。结果:(1)高胆固醇饲料喂养20天,小鼠血清TC,MDA升高,HDL-c和SOD降低,高脂血症模型建造成功,肝重量增加,有脂肪肝出现,胸腺重量减轻.(2)有氧运动降低TC,升高MDA和HDL-C,肝重量不减轻,脂肪肝存在.(3)有氧运动合用Gin时, TC, TG和 MDA均降低(P< 0.05), HDL-c和SOD显著升高(P<0.01),肝重量减轻和胸腺重量接近正常,脂肪肝消失.结论:单纯有氧运动可在一定程度上降低血脂,但不能很好调节脂质代谢,当有氧运动合用Gin时,其降脂调脂和抗氧化作用才更明显,并可能有一定的减慢机体衰老过程的作用。  相似文献   

9.
丹皮总苷对化学性肝损伤保护作用机制   总被引:7,自引:0,他引:7  
目的研究丹皮总苷(totalglucosidesofmuoltancortes,TGM)对CCl4和D Gal N致小鼠化学性肝损伤的保护作用机制。方法采用CCl4和D Gal N所致小鼠化学性肝损伤模型进行研究,用TBA法和DTNB法测定MDA和GSH Px。结果TGM具有促进肝脏糖原合成和提高血清蛋白含量的作用(P<001),可明显降低肝匀浆脂质过氧化产物丙二醛(MDA)的含量(P<001)及提高血清和肝脏谷胱甘肽过氧化物酶活力(P<001),且可缩短CCl4中毒小鼠ip戊巴比妥钠后的睡眠时间(P<001)。结论TGM可能通过影响肝脏代谢机能,增强抗氧化作用,加强解毒能力机制发挥抗损伤作用。  相似文献   

10.
三硝基甲苯对大鼠肾脏某些抗氧化酶活性的影响   总被引:1,自引:1,他引:0  
本研究观察了三硝基甲苯(TNT)不同剂量染毒和阳性对照安妥明处理对大鼠肾组织匀浆过氧化氢酶(CAT)、谷胱甘肽过氧化物酶(GSH-PX)、超氧化物歧化酶(SOD)活性及肾组织蛋白含量的影响。结果表明,TNT染毒组、阳性对照组大鼠肾匀浆CAT与GSH-PX活性显著高于对照组(P<0.05),而肾蛋白含量显著降低(P<0.05),表明TNT染毒和安妥明处理均可诱导肾组织过氧化氢生成。推测TNT可能具有诱发肾脏过氧化物小体增生作用  相似文献   

11.
Dichloromethane (DCM) is metabolically converted to carbon monoxide mostly by CYP2E1 in liver, resulting in elevation of blood carboxyhemoglobin (COHb) levels. We investigated the effects of a subtoxic dose of acetaminophen (APAP) on the metabolic elimination of DCM and COHb elevation in adult female rats. APAP, at 500 mg/kg i.p., was not hepatotoxic as measured by a lack of change in serum aspartate aminotransferase, alanine aminotransferase, and sorbitol dehydrogenase activities. In rats pretreated with APAP at this dose, the COHb elevation resulting from administration of DCM (3 mmol/kg i.p.) was enhanced significantly. Also blood DCM levels were reduced, and its disappearance from blood appeared to be increased. Hepatic CYP2E1-mediated activities measured with chlorzoxazone, p-nitrophenol, and p-nitroanisole as substrates were all induced markedly in microsomes of rats treated with APAP. Aminopyrine N-demethylase activity was also increased slightly, but significantly. Western blot analysis showed that APAP treatment induced the expression of CYP2E1 and CYP3A proteins. Neither hepatic glutathione contents nor glutathione S-transferase activity was changed by the dose of APAP used. The results indicate that, contrary to the well known hepatotoxic effects of this drug at large doses, a subtoxic dose of APAP may induce CYP2E1, and to a lesser degree, CYP3A expression. This is the first report that APAP can increase cytochrome P450 (P450)-mediated hepatic metabolism and the resulting toxicity of a xenobiotic in the whole animal. The pharmacological/toxicological significance of induction of P450s by a subtoxic dose of APAP is discussed.  相似文献   

12.
Acetaminophen (APAP) is a widely used analgesic and antipyretic that can lead to severe liver damage when taken at excessive doses. APAP toxicity results when cytochrome P450-generated APAP metabolites trigger an oxidative stress and covalently modify target proteins. APAP has also been reported to inhibit cells from completing S-phase through a cytochrome P450-independent mechanism, raising the possibility that APAP may directly suppress liver regeneration and repair. Here we show that APAP also inhibits entrance of Hepa 1-6 cells into the cell cycle by blocking a number of events associated with the G0-G1 transition. We have found that APAP inhibits serum growth factor activation of c-myc expression, NF-kappaB DNA binding, and Raf kinase. Therefore, the ability of APAP to inhibit passage of cells through both G1 and S phases might interfere with organ regeneration and thus exacerbate acute liver damage caused by APAP.  相似文献   

13.
Acetaminophen (APAP), a widely used analgesic and antipyretic agent, can cause acute hepatic necrosis in both humans and experimental animals when consumed in large doses. It is generally accepted that N-acetyl-p-benzoquinone imine (NAPQI) is the toxic, reactive intermediate whose formation from APAP is mediated by cytochrome P450. Several forms of P450 in humans, including 2E1, 1A2, 2A6, 3A4, have been shown to catalyze the oxidation of APAP to NAPQI. We now present evidence which demonstrates that human cytochrome P450 2D6 (CYP2D6) is also involved in the bioactivation of APAP. The formation of NAPQI from APAP by cDNA-expressed CYP2D6 was examined. K(m) and V(max) values were 1.76 mM and 3.02 nmol/min/nmol of P450, respectively, such that the efficiency of CYP2D6 in the conversion of APAP to NAPQI is approximately one-third of that of CYP2E1. The contribution of CYP2D6 to the total formation of NAPQI from APAP (1 mM) in human liver was investigated using quinidine (1 microm) as a CYP2D6-specific inhibitor, and varied from 4.5 to 22.4% among 10 livers, with an average at 12.6%. The correlation between the contribution of CYP2D6 to NAPQI formation in human liver microsomes and the CYP2D6 activity probed by the O-demethylation of dextromethorphan was studied, and found to be strong (r(2) = 0.85), and significant (P <.0001). Our findings indicate that CYP2D6, one of the major P450 isoforms in humans and also one of the pharmacogenetically important isoforms, may contribute significantly to the formation of the cytotoxic metabolite NAPQI, especially in CYP2D6 ultra-rapid and extensive metabolizers and at toxic doses of APAP when plasma APAP concentrations reach 2 mM or more.  相似文献   

14.
Paracetamol (acetaminophen, APAP) liver and kidney cytotoxicity is associated with bioactivation by P450 and/or prostaglandin H synthetase (PGHS) to a reactive metabolite, which depletes GSH, covalently binds to proteins, and leads to oxidative stress. Although APAP may also damage the lung, little is known about the mechanism by which this occurs. We studied the in vitro 24-hr-old type II pneumocytes. A time- and concentration-dependent decrease in intracellular GSH occurred in freshly isolated type II pneumocytes and alveolar macrophages exposed to subtoxic (相似文献   

15.
Acute viral infection has long been recognized to down-regulate cytochrome P-450 enzymes and subsequently to result in changes in the pharmacological and toxicological responses to xenobiotics. In our previous research, chronic retrovirus infection induced by inoculating a susceptible strain of mice with LP-BM5 murine leukaemia virus (MuLV) was found to suppress acetaminophen (APAP) induced liver injury. In the present study, we aimed to examine the influence of chronic retrovirus infection and its associated immune dysfunction on the activities of a number of cytochrome P-450 isozymes and the P-450-mediated activation of APAP in mouse liver microsomes. Liver microsomes prepared from female C57BL/6 mice at 8 and 16 weeks after LP-BM5 MuLV inoculation as well as from age-matched controls were used in the study. The catalytic activities of the cytochrome P-450 isozymes 1A family and 2E1, catalysts for the activation of APAP, were measured in different microsomal preparations using O-dealkylation of alkoxyresorufin homologues and oxidation of p -nitrophenol, respectively, as the metabolic markers. The formation of the reactive APAP metabolite trapped as glutathione conjugate in the microsomal preparations was also determined. We demonstrated that there were variable changes in total hepatic P-450 levels and in the activities of a number of P-450 isozymes in animals with chronic retrovirus infection and immune dysfunction. Such changes seemed to be dependent on the stage of the disease and to have resulted in increases or minimal changes in the rate of APAP activation in hepatic microsomes collected from this animal model. This suggests that the P-450-mediated activation of APAP was not down-regulated in animals with chronic retrovirus infection. Enhanced elimination of APAP by detoxification metabolic pathways is more likely to be responsible for the increased resistance to APAP-induced hepatotoxicity observed in our previous research in animals with chronic retrovirus infection. © 1998 John Wiley & Sons, Ltd.  相似文献   

16.
Acetaminophen (APAP) hepatotoxicity results from cytochrome P450 metabolism of APAP to the toxic metabolite, n-acetyl-benzoquinone imine (NAPQI), which reacts with cysteinyl residues to form APAP adducts and initiates cell injury. As APAP is commonly used during viral illnesses there has been concern that APAP injury may be additive to that of viral hepatitis, leading physicians to advise against its use in such patients; this has not been investigated experimentally. We infected C57BL/6 male mice with replication-deficient adenovirus to produce moderately severe acute viral hepatitis and observed that APAP doses that were hepatotoxic or lethal in control mice produced neither death nor additional increase in serum ALT when administered to infected mice at the peak of virus-induced liver injury. Moreover, the concentration of hepatic APAP-protein adducts formed in these mice was only 10% that in control mice. Protection from APAP hepatotoxicity also was observed earlier in the course of infection, prior to the peak virus-induced ALT rise. Hepatic glutathione limits APAP-protein adduct formation but glutathione levels were similar in control and infected mice. Cyp1a2 (E.C. 1.14.14.1) and Cyp2e1 (E.C. 1.14.13.n7) mRNA expression decreased by 3 days post-infection and hepatic Cyp2e1 protein levels were reduced almost 90% at 7 days, when adduct formation was maximally inhibited. In vitro, hepatocytes from virally infected mice also were resistant to APAP-induced injury but sensitive to NAPQI. Rather than potentiating APAP-induced liver injury, acute viral hepatitis in this model resulted in selective down-regulation of APAP metabolizing P450s in liver and decreased the risk of APAP hepatotoxicity.  相似文献   

17.
Nuclear receptors, including constitutive androstane receptor, pregnane X receptor, and retinoid X receptor (RXR), modulate acetaminophen (APAP)-induced hepatotoxicity by regulating the expression of phase I cytochrome P450 (P450) genes. It has not been fully resolved, however, whether they regulate APAP detoxification at the phase II level. The aim of the current study was to evaluate the role of RXRalpha in phase II enzyme-mediated detoxification of APAP. Wild-type and hepatocyte-specific RXRalpha knockout mice were treated with a toxic dose of APAP (500 mg/kg i.p.). Mutant mice were protected from APAP-induced hepatotoxicity, even though basal liver glutathione (GSH) levels were significantly lower in mutant mice compared with those of wild-type mice. High-performance liquid chromatography analysis of APAP metabolites revealed significantly greater levels of APAP-GSH conjugates in livers and bile of mutant mice compared with those of wild-type mice. Furthermore, hepatocyte RXRalpha deficiency altered the gene expression profile of the glutathione S-transferase (Gst) family. Basal expression of 13 of 15 Gst genes studied was altered in hepatocyte-specific RXRalpha-deficient mice. This probably led to enhanced APAP-GSH conjugation and reduced accumulation of N-acetyl-p-benzoquinone imine, a toxic electrophile that is produced by biotransformation of APAP by phase I P450 enzymes. In conclusion, the data presented in this study define an RXRalpha-Gst regulatory network that controls APAP-GSH conjugation. This report reveals a potential novel strategy to enhance the detoxification of APAP or other xenobiotics by manipulating Gst activity through RXRalpha-mediated pathways.  相似文献   

18.
Geranylgeranylacetone (GGA), an anti-ulcer drug, has been reported to induce heat shock protein (HSP) 70 in several animal organs. The present study was performed to determine whether GGA protects mouse liver against acetaminophen (APAP)-induced injury and whether it has potential as a therapeutic agent for APAP overdose. Hepatic damage was induced by single oral administration of APAP (500 mg/kg). GGA at 400 mg/kg was given orally 4 or 8h before, or 0.5h after APAP administration. Treatment of mice with GGA 4h before or 0.5h after APAP administration suppressed increases in transaminase activities and ammonia content in blood as well as hepatic necrosis. Such GGA treatment significantly increased hepatic HSP70 accumulation after APAP administration. Furthermore, GGA inhibited increases in hepatic lipid peroxide content and hepatic myeloperoxidase activity after APAP administration. In contrast, GGA neither inhibited hepatic cytochrome P450 2E1 activity nor suppressed hepatic glutathione depletion after APAP administration. The protective effect of GGA treatment 4h before APAP on hepatotoxicity induced by APAP was completely inhibited with quercetin, known as an HSP inhibitor. In conclusion, GGA has been identified as a new antidote to APAP injury, acting by induction of HSP70. The potential of GGA as a therapeutic tool is strongly supported by its ability to inhibit hepatic injury even when administered after ingestion of APAP.  相似文献   

19.
The metabolism zonation in liver lobules is well known yet its incorporation into the mathematical models of acetaminophen (APAP) metabolism is still primitive – only the oxidation pathway via reaction with the cytochrome P450 (CYP450) has been considered, yet the zonal heterogeneity exhibits in all three pathways including sulphation, glucuronidation and oxidation. In this paper we present a novel computational method where an intracellular APAP metabolism model is integrated into a Finite Element Model (FEM) of sinusoids, and the zonal heterogeneity in three metabolism pathways are all incorporated. We demonstrate that the degradation of APAP, detoxification via glutathione (GSH) and the formation of hepatotoxicity, are all affected profoundly by the zonal difference. Specifically, glucuronidation plays a major role in the degradation of APAP. Generation of GSH, its conjugation with the toxic NAPQI and the spatial distribution of CYP450 combined together determine the toxicity of APAP. We suggest that the current platform be used for further hepatotoxicity study of APAP by incorporating other heterogeneity factors.  相似文献   

20.
Prevention of acetaminophen-induced hepatotoxicity by dimethyl sulfoxide   总被引:1,自引:0,他引:1  
Y Park  R D Smith  A B Combs  J P Kehrer 《Toxicology》1988,52(1-2):165-175
Dimethyl sulfoxide (DMSO) has previously been shown to protect against acetaminophen (APAP)-induced hepatotoxicity, but the mechanism of this effect was not clear. Treatment of mice with 1 mg/kg DMSO 4 h before 250 mg/kg APAP resulted in significantly less hepatotoxicity than with APAP alone, as measured by serum glutamic pyruvic transaminase (SGPT) content 24 h after APAP. Protection was also evident when 1 ml/kg DMSO was given 4, but not 8 h after 250 mg/kg APAP. The APAP-induced depletion of liver glutathione was prevented in mice pretreated with DMSO, although DMSO alone had no effect on liver glutathione levels. The hepatic concentration of cytochrome P-450 (P450) 4 h after treatment of mice with 1 ml/kg DMSO, was significantly decreased compared to saline-treated animals. However, while this DMSO pretreatment significantly decreased the activity of cytochrome P-450-linked aminopyrine-N-demethylase, it increased the activity of aniline hydroxylase. Covalent binding of [14C]APAP to hepatic protein in vivo was significantly decreased in mice pretreated with DMSO. Covalent binding of [14C]APAP to hepatic microsomal protein in vitro was not significantly altered after in vivo treatment with DMSO. However, the presence of DMSO in the in vitro incubation mixture significantly decreased covalent binding of [14C]APAP in a dose-dependent manner compared to microsomal fractions from untreated, saline-treated or DMSO pretreated animals. These data suggest that the DMSO-induced alterations in cytochrome P-450 content and activity may not be the cause of the observed protective action of this chemical. The ability to competitively inhibit APAP bioactivation or to directly scavenge free radicals produced during APAP metabolism, including the activated species which covalently binds to protein, may account for the hepatoprotection afforded by DMSO.  相似文献   

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