CoQ_（10）对醋氨酚肝毒性的保护作用探讨

＊Ｐ＜０．００１从表３可见，ＣｏＱ１０高低剂量组肝匀浆ＣｙｔＰ４５０含量与ｎＳ对照组比较没有明显差异（Ｐ＞０．０５），而苯巴比妥钠组小鼠肝匀浆ＣｙｔＰ４５０含量较ＮＳ对照组及高低剂量组显著升高，有非常显著性差异（Ｐ＜０．００１）。本巴比妥钠为肝药酶诱导剂，其阳性结果证明此实验方法可靠，也证明ＣｏＱ１０对肝细胞ＣｙｔＰ４５０含量没有影响。３讨论本实验结果表明：小鼠用ＣｏＱ１０作预处理，确能保护超量ＡＡＰ对肝脏的损伤作用；同时能使ＡＡＰ血清浓度明显升高，而对肝细胞ＣｙｔＰ４５０含量则无影响。据文献报道，超ｔＡＡＰ进入肝细胞微粒体后，通过肝药酶代谢产出大量毒性中间产物，因而引起肝损害甚至肝坏死［７］。ＣｏＱ１０能防止这一毒性效应，通过稳定肝细胞微粒体膜或抑制肝药酶活住，均可达此目的．上述实验结果．均提示ＣｏＱ１０的作用途径可能是稳定肝细胞微粒体膜，使ＡＡＰ进入微粒体数量减少，因而毒性中间代射产物生成减少，使肝细胞损伤减轻。参考文献     

氰戊菊酯可诱导大鼠肝脏 P450 2B1/2B2

氰戊菊酯可诱导大鼠肝脏Ｐ４５０２Ｂ１／２Ｂ２张伟华贺锡雯（中国预防医学科学院劳动卫生与职业病研究所，北京１０００５０）氰戊菊酯（Ｆｅｎ）是一类新型的拟除虫菊酯类农药．本文就Ｆｅｎ对肝脏ＣｙｔＰ４５０酶系含量的影响及其特异性进行了探讨，为Ｆｅｎ长期效应...     

姜黄素对大鼠肝CytP450系统及谷胱甘肽—S—转移酶活性的影响

姜黄素是从植物姜黄中提取的一种酚性食用色素。近年来的研究表明：姜黄素除有抗致突变、清除自由基、防止致癌过程中所造成的ＤＮＡ损伤外，尚有拮抗苯并（ａ）芘所致小鼠前胃癌的作用。为了进一步探讨姜黄素的抑癌机理，用姜黄素给雄性ＷＫＡ大鼠连续灌胃６ｄ，以观察姜黄素对大鼠肝微粒体细胞色素Ｐ４５０总量（ＣｙｔＰ４５０）、细胞色素ｂ５、苯胺羟化酶（ＡＨ）、对硝基苯酚（ＰＮＰ）羟化酶、７－乙氧基香豆素脱乙基酶（ＥＣＯＤ）活力以及肝谷胱甘肽－Ｓ－转移酶（ＧＳＴ）活力的影响。结果表明：姜黄素能使ＣｙｔＰ４５０总量及ＧＳＴ活性增高；对ＡＨ的活性有明显抑制作用。说明姜黄素可能通过诱导或抑制Ｉ相酶反应，诱导Ⅱ相酶反应来发挥其抑癌作用的。     

P450ⅢA在2,4,5—三氟苯胺代谢生成一氧化碳中起主导…

２，４，５－三氟苯胺（２，４，５－ＴＦＡ）与空气氧，ＮＡＤＰＨ及地塞米松（ＤＥＸ）预处理的大鼠肝微粒体共温育，可生成大量的一氧化碳（ＣＯ）。但是，未处理或β－萘黄酮预处理的大鼠肝微粒体却无上述能力。与ＤＥＸ相比，苯巴比妥（ＰＢ）诱导的鼠肝微粒体使２，４，５－ＴＦＡ生成ＣＯ的能力仅为前者的１／４。Ｐ４５０ⅢＡ是ＤＥＸ所诱导的最主要的Ｐ４５０亚族，亦能为ＰＢ所诱导，因而在Ｐ４５０ⅢＡ对２，４，５－ＴＦ     

单克隆抗体技术在细胞色素P450研究中的应用

单克隆抗体技术在细胞色素Ｐ４５０研究中的应用石年综述刘毓谷审校细胞色素Ｐ４５０酶系（ＣｙｔｏｃｈｒｏｍｅＰ４５０，ＣｙｔＰ５０）是机体中催化外来化合物进行代谢的主要酶系。其对机体有两方面的意义，一是通过氧化和结合反应，使外来化合物安全地排出体外；二是...     

心血管药物速效救心丸和通心络胶囊对大鼠细胞色素P450酶的影响

目的:观察速效救心丸和通心络胶囊对大鼠药物代谢酶细胞色素P450(CYP450)的影响。方法:给予大鼠试验药物后制备肝及小肠微粒体,CO还原差示光谱法测定肝微粒体CYP450含量,蛋白免疫印迹法检测肝微粒体中CYP1A2、CYP2C11、CYP2E1、CYP3A和肠微粒体中CYP3A蛋白的表达量。结果:速效救心丸组和通心络胶囊组与空白对照组比较,大鼠肝脏CYP450含量无显著变化(P>0.05);但是West-ern blotting实验对肝脏和肠道中多种CYP450酶表达量测定的结果显示,速效救心丸可诱导肝脏CYP1A2表达,但抑制肝脏CYP2C11和肠道CYP3A表达(P<0.05);通心络胶囊可诱导大鼠肝脏CYP1A2、CYP2E1蛋白表达(P<0.05)。结论:速效救心丸和通心络胶囊对大鼠肝脏CYP450酶总量无影响,但是,在蛋白质水平对特定亚型蛋白的表达量有影响,由此可能引发的药物相互作用不容忽视。     

肝细胞色素P_(450)与药物代谢的研究进展

外源性化合物特别是药物进入体内后 ,很多都经过肝脏代谢 ,而肝药酶ＣＹＰ４５０ 是肝代谢药物的主要酶系。ＣＹＰ４５０ 同工酶能代谢药物使其失活 ,也能使某些无活性的物质转化成活性物质而产生药理作用或毒性。肝脏中ＣＹＰ４５０ 的不同类型及不同含量将直接影响药物的代谢转化、药物间相互作用等 ;同时 ,外源性化合物也能影响ＣＹＰ４５０ 在肝脏的表达 ,从而诱导或抑制其活性。了解ＣＹＰ４５０ 的特性 ,调控ＣＹＰ４５０ 的表达水平有助于临床合理用药及预防疾病 ,也一直是该领域的研究热点之一。１肝细胞色素Ｐ４５０ 同工酶迄今为…     

对氯邻甲苯胺代谢中间体络合物作为一种新的可表征P450ⅡB…

正常大鼠肝微粒体与对氯邻甲苯胺温育不形成Ｐ４５０代谢中间体络合物，比苯巴比脂或多氯联苯１２５４预处理大鼠，显增高肝微粒体与ＰＣＴ形成ＭＩ络合物的能力，而用β－萘黄酮或地塞米松诱导大鼠却无类似影响。考虑到Ｐ４５０ⅡＢ亚族既可为ＰＢ亦可为ＡＲＯ所诱导增加，ＰＣＴ－ＭＩ事物生成或许可用来表征Ｐ４５０ⅡＢ。     

P450ⅢA在2，4，5－三氟苯胺代谢生—氧化碳中起主导作用

２，４，５－三氟苯胺（２，４，５－ＴＦＡ）与空气氧，ＮＡＤＰＨ及地塞米松（ＤＥＸ）预处理的大鼠肝微粒体共温育，可生成大量的一氧化碳（ＣＯ）．但是，未处理或β－萘黄酮预处理的大鼠肝微粒体却无上述能力。与ＤＥＸ相比，苯巴比妥（ＰＢ）诱导的鼠肝微粒体使２，４，５－ＴＦＡ生成ＣＯ的能力仅为前者的１／４．Ｐ４５０ⅢＡ是ＤＥＸ所诱导的最主要的Ｐ４５０亚族，亦能为ＰＢ所诱导，因而在Ｐ４５０ⅢＡ对２，４，５－ＴＦＡ降解为ＣＯ中或许起主要作用，为证实这一推论，我们研究了ＣＯ生成能力与Ｐ４５０不同亚族的特征催化活性间的相关性。在所选用的红霉素氮上去甲基化，三乙酰竹桃霉素（ＴＡＯ）代谢中间体（ＭＩ）络合物生成能力，对氨基苯甲酸叔丁酯ＭＩ络合物生成能力，戊氧基异吩唑氧上去烷基化，乙氧基异吩唑氧上去乙基化，以及氨基比林氮上去甲基化等活性指标中，仅表征Ｐ４５０ⅢＡ的活性指标──ＴＡＯ－ＭＩ络合物生成能力及红霉素氮上去甲基酶活性，与ＣＯ的生成能力明显相关。给ＤＥＸ诱导的大鼠以Ｐ４５０ⅢＡ的抑制剂ＴＡＯ处理，鼠肝微粒体的Ｐ４５０含量，ＴＡＯ－ＭＩ络合物生成能力，红霉素氮上去甲基化作用，及ＣＯ生成能力的丢失程度相近。上述结果表明，Ｐ４５０Ⅲ?     

消草磷破坏肝脏细胞色素P450

消草磷与经苯巴比妥预处理大鼠的肝微粒体一起温育,在有NADPH存在时,最多可使肝微粒体细胞色素P450丢失58％左右。苯巴比妥预处理大鼠经ip或po 1.0g/kg消草磷,18h后肝微粒体P450将丢失40％左右,但用还原态P450甲吡酮络合物生成量估算剩余P450的亚族组成却无显著变化。此现象似提示消草磷的体内活性代谢物之一或许是硫化氢。尽管高剂量消草磷体内与体外均导致P450破坏,但低剂量(如 0.1g/kg)短期接触却不致诱发以肝脏P450丢失为特征的特殊肝脏毒性。     

抗组胺药敏感性的细胞色素P450研究进展

HP450具有细胞色素P450特征和抗组胺药敏感的双重性,它在不同的大鼠肝脏疾病模型中有明显的变化规律,与肝脏疾病的发展具有一定的相关性,在肝癌发生过程中HP450基因的转录及表达均发生了变化。HP450有可能作为诊断肝癌的新指标,在预防和治疗肝癌中可能作为一个新靶点。     

CYP2C19基因多态性与中国汉族人群急性冠脉综合征的相关性研究

目的：探讨细胞色素 P450（CYP）2C19基因常见多态性位点与中国汉族人群急性冠脉综合征（ACS）的相关性。方法提取206例 ACS 患者和232例对照者外周血 DNA,采用 DNA 微阵列芯片法对 CYP2C19*2（681G ＞A）、CYP2C19*3（636G ＞ A）进行基因型检测,对比2组间及不同 ACS 分型患者间基因型及等位基因突变频率的分布差异,同时运用 Logistic 回归分析探讨 ACS 发生的独立危险因素。结果 CYP2C19*1、*2、*3分布比例依次为64.38％、29.46％和6.16％,不同性别人群的等位基因及基因型分布差异无统计学意义（ P ＞0.05）。ACS 组CYP2C19*1/*1的分布频率明显少于对照组（ P ＜0.05）,但 CYP2C19*1/*2与 CYP2C19*1/*3的分布频率之和明显高于对照组（ P ＜0.05）。CYP2C19*1/*1所占比例 STEMI 组明显低于 NSTEMI 组（ P ＜0.01）,CYP2C19*1/*2的分布频率 NSTEMI 组最低,且与 STEMI 及 UA 组间差异均有统计学意义（ P ＜0.01）。Logistic 回归分析显示CYP2C19*2（681G ＞ A）GA 基因型是中国汉族人群 ACS 发生的独立危险因素（OR ＝5.97,95％ CI 为1.09～12.35, P ＝0.007）。结论 CYP2C19*2（681G ＞ A）GA 基因型可能与中国汉族人群 ACS 风险增高有关。     

芳香化酶P450在子宫内膜增殖及癌变组织中的表达及意义

目的探讨芳香化酶P450在子宫内膜增殖、非典型增殖及癌变组织中的表达。方法应用免疫组织化学SP法对子宫内膜增殖、非典型增殖及癌变子宫内膜(观察组)148例芳香化酶P450的表达进行研究,并设正常增殖期子宫内膜37名为对照组。结果对照组无芳香化酶P450表达,观察组芳香化酶P450呈阳性表达,表达率分别为45%、72%、75%,两组差异有统计学意义;非典型组与癌变组阳性表达率差异无统计学意义,但表达的阳性细胞数差异有统计学意义。结论芳香化酶P450的异常表达与子宫内膜增殖癌变的发生、发展有关,组织学异型性与阳性表达率增高有关;提示芳香化酶P450可能是促使子宫内膜细胞增殖及恶变的促进因素之一。     

Induction of P450 3A1/2 and 2C6 by gemfibrozil in Sprague-Dawley rats

Fibrates are a group of peroxisome proliferator-activated receptor α agonists used in the treatment of dyslipidemia; however, they have been reported to cause species-related hepatocarcinogenesis and clinical myotoxicity. Gemfibrozil is one of the most commonly used fibrates, and it shows the highest risk for myotoxicity among the fibrates. The inhibitory drug-drug interaction mechanism associated with gemfibrozil has been explored recently, and the induction of human P450 3A4 and 2C8 has been reported. In this study, in vivo induction of rat P450 by gemfibrozil was studied in Sprague-Dawley rats. After the rats were dosed with gemfibrozil by oral gavage, microsomes were prepared. The metabolic activities of P450 3A1/2, 2C6, and 2D2 were assayed using probe substrates, and the systemic concentration of gemfibrozil during its administration was determined. P450 3A1/2 and 2C6 activities were induced 32-77% in the rats by gemfibrozil when the exposure concentration was in the clinical range. These data indicate that the inducibility of homologous P450 isoforms by gemfibrozil is similar in Sprague-Dawley rats and in humans. Inductive drug-drug interactions and inhibitory actions are involved in the co-administration of gemfibrozil with other drugs, which suggests the relevance for a fibrate-toxicology investigation.     

卤酚化合物LM49对大鼠肝微粒体细胞色素P450的影响

目的研究LM49对大鼠肝微粒体蛋白及细胞色素P450含量的影响。方法将大鼠分成空白对照组、溶剂对照组、阳性对照组(苯巴比妥组、地塞米松组、β-萘黄酮组)、LM49低、中、高剂量组。给药后采用超速离心法制备大鼠肝微粒体;BCA法测定大鼠肝微粒体蛋白浓度;Omura and Sato法测定大鼠肝微粒体细胞色素P450的含量。结果 给予不同剂量的LM49后,大鼠肝微粒体的蛋白及细胞色素P450含量均明显降低。低、中、高剂量组与对照组比较差异有统计学意义(P<0.05)。结论 LM49对大鼠肝微粒体细胞色素P450具有一定的抑制作用,可能引起肝药酶对某些药物代谢的改变。     

The role of renal proximal tubule P450 enzymes in chloroform-induced nephrotoxicity: Utility of renal specific P450 reductase knockout mouse models

The kidney is a primary target for numerous toxic compounds. Cytochrome P450 enzymes (P450) are responsible for the metabolic activation of various chemical compounds, and in the kidney are predominantly expressed in proximal tubules. The aim of this study was to test the hypothesis that renal proximal tubular P450s are critical for nephrotoxicity caused by chemicals such as chloroform. We developed two new mouse models, one having proximal tubule-specific deletion of the cytochrome P450 reductase (Cpr) gene (the enzyme required for all microsomal P450 activities), designated proximal tubule-Cpr-null (PTCN), and the other having proximal tubule-specific rescue of CPR activity with the global suppression of CPR activity in all extra-proximal tubular tissues, designated extra-proximal tubule-Cpr-low (XPT-CL). The PTCN, XPT-CL, Cpr-low (CL), and wild-type (WT) mice were treated with a single oral dose of chloroform at 200 mg/kg. Blood, liver and kidney samples were obtained at 24 h after the treatment. Renal toxicity was assessed by measuring BUN and creatinine levels, and by pathological examination. The blood and tissue levels of chloroform were determined. The severity of toxicity was less in PTCN and CL mice, compared with that of WT and XPT-CL mice. There were no significant differences in chloroform levels in the blood, liver, or kidney, between PTCN and WT mice, or between XPT-CL and CL mice. These findings indicate that local P450-dependent activities play an important role in the nephrotoxicity induced by chloroform. Our results also demonstrate the usefulness of these novel mouse models for studies of chemical-induced kidney toxicity.     

Inhibition of Cytochromes P450: Existing and New Promising Therapeutic Targets

Mammalian cytochromes P450 have been shown to play highly important roles in the metabolism of drugs and xenobiotics as well as in the biosynthesis of a variety of endogenous compounds, many of them displaying hormonal function. The role of P450s as therapeutic targets is still inadequately recognized although several P450 inhibitors became efficient drugs that even reached blockbuster status. Here, we try to give a comprehensive overview on cytochromes P450s, which are already well-established targets – particularly focussing on the treatment of infectious diseases, metabolic disorders and cancer – and on those, which have a high potential to become successful targets. In addition, the design of inhibitors of cytochromes P450 will be discussed.     

葛根素对慢性低氧性肺动脉高压大鼠肺血管重构的影响

目的　观察葛根素对慢性低氧性肺动脉高压大鼠肺动脉压力和肺血管重构的调节作用。方法　SD大鼠 3 0只随机分为 :正常对照组 (NC)、低氧组 (HH)、低氧加葛根素组(HP)。分别测定平均肺动脉压 (mPAP) ;肺组织匀浆超氧化物歧化酶 (SOD)活性、丙二醛 (MDA )含量 ;血浆内皮素 1(ET 1)、一氧化氮代谢产物 (NO-x )含量 ;弹力纤维染色法测定肌型动脉百分比 ,肺中、小动脉相对中膜面积 (RMP)、厚度 (RMT) ;采用免疫组织化学法检测Ⅰ、Ⅲ型胶原蛋白的表达 ;核酸原位杂交法检测肺动脉Ⅰ型前胶原mRNA表达。结果　HP组与HH组相比 :①mPAP降低 (P <0 0 1) ;平均颈动脉压 (mCAP)差异无显著性 (P >0 0 5) ;②肺组织匀浆SOD活性升高 (P <0 0 1) ,MDA含量降低 (P <0 0 1) ;③血浆ET 1浓度降低 (P <0 0 1) ,NO-x 含量升高 (P <0 0 1) ,ET 1/NO-x 比值降低 (P <0 0 1) ;④肌型动脉百分比和肺中、小动脉RMP及RMT降低 (P <0 0 1) ;⑤肺细小动脉Ⅰ型胶原蛋白及Ⅰ型前胶原mRNA表达降低 (P <0 0 1) ,而Ⅲ胶原蛋白平均吸光度值差异无显著性 (P >0 0 5)。结论　葛根素注射液可预防慢性低氧性肺动脉高压大鼠的形成 ,减轻肺血管重构。其机制可能与抗氧化作用 ,调节肺动脉胶原蛋白合成以及恢复ET 1/NO的失衡等有关     

芳香化酶P450在子宫内膜增殖及非典型增殖组织中的表达

目的探讨芳香化酶P450在子宫内膜增殖和非典型增殖中的诊断和治疗价值。方法应用免疫组织化学SP法对子宫内膜单纯性增殖30例、复杂性增殖32例及非典型增殖54例中的芳香化酶P450、雌激素受体(ER)及孕激素受体(PR)的表达进行检测,并结合临床过程进行分析。结果在正常增生期子宫内膜组织中无芳香化酶P450的表达,子宫内膜增殖(单纯性增殖、复杂性增殖、非典型增殖)组织中芳香化酶P450呈阳性表达,阳性表达率分别为41.1%、46.1%、73.2%,阳性表达率差异有统计学意义(χ2=46.69,P<0.01);ER及PR的表达与子宫内膜组织细胞的异型性程度无关;芳香化酶P450与ER、PR在子宫内膜增殖组织中(单纯性增殖、复杂性增殖、非典型增殖)的表达不存在相关性。结论芳香化酶P450可能是子宫内膜细胞增殖及恶变的促进因素之一,并可能成为子宫内膜早期癌变的生物学标记物。ER的阳性表达说明子宫内膜增殖的发生与子宫内膜局部雌激素的刺激作用有关。PR的阳性表达可以作为子宫内膜增殖保守治疗中估计预后的有效指标。     

The Hepatic and Intestinal Metabolic Activities of P450 in Rats with Surgery- and Drug-Induced Renal Dysfunction

Purpose. The hepatic and intestinal metabolic activities of P450 were evaluated in rats with surgery- and drug-induced renal dysfunction. Methods. Renal failure was induced by five-sixths nephrectomy (NR), bilateral ureter ligation (BUL), the intramuscular injection of glycerol (GL), and the intraperitoneal injection of cisplatin (CDDP). Phenytoin 4-hydroxylation, debrisoquine 4-hydroxylation, and testosterone 6-hydroxylation were estimated to evaluate the metabolic activities of cytochrome P450 (CYP) 2C, 2D, and 3A, respectively. Results. The hepatic CYP3A metabolic activities were decreased by 65.9% and 60.2% in NR and GL rats, respectively. The hepatic CYP2C metabolic activity was decreased by 48.8% in CDDP rats. No alteration in hepatic drug-metabolizing activities was observed in BUL rats. On the other hand, the intestinal CYP3A metabolic activity was weakly increased in GL rats but not significantly altered in NR, CDDP, and BUL rats. Conclusions. This study suggested (a) that only selected P450 metabolic activity in the liver is decreased in renal failure, (b) that extent of the decrease in hepatic metabolic activities of P450 is dependent on the etiology of renal failure, and (c) that alteration of CYP3A metabolic activity in the intestine is not always correlated with that in the liver.