口服黄芩素对大鼠药物代谢酶的影响

目的:考察口服黄芩素对大鼠肝细胞色素P450(CYP450)、谷胱甘肽-S-转移酶(GST)和尿苷二磷酸-葡萄糖醛酸转移酶(UGT)活性的影响。方法:大鼠连续7 d口服200 mg.kg-1黄芩素后,差速离心法制备肝微粒体和肝胞浆,采用特异性探针底物法测定肝微粒体CYP450酶系6种同工酶活性的变化,采用比色法检测GST和UGT活性的变化。结果:大鼠口服黄芩素对CYP2C9,CYP2E1,GST和UGT有显著的抑制作用,抑制率分别为26.76%,29.12%,37.45%和70.86%(P<0.05或0.01),对CYP1A2,CYP2C19,CYP2D6和CYP3A4没有明显的影响。结论:其他药物与黄芩素合用时,需考虑可能由于代谢酶活性变化引起的药物相互作用。     

介导候选药代谢的肝细胞色素P450酶表型鉴定的定性和定量方法

新药研发需要对候选药物的代谢途径、每个代谢途径对总清除率的贡献以及参与代谢的酶进行详细研究。候选药物经过肝细胞色素P450(CYP)酶代谢的比例(f_m)可以用放射性同位素标记的方法在人体水平测定,而肝中某酶亚型的代谢占总的CYP参与代谢的比例(f_CYPi)可以用体外酶表型鉴定的方法来测定,这两个参数的乘积f_m×f_CYPi即为某个CYP酶亚型代谢参与某候选药物体内清除的百分比,对研究体内药物-药物相互作用具有重要意义。本文从定性和定量两方面综述体外酶表型鉴定的研究方法。     

补骨脂酚在大鼠和人肝微粒体中细胞色素P450酶和尿苷二磷酸葡萄糖醛酸转移酶代谢稳定性及性别差异

目的探究补骨脂酚在大鼠和人肝微粒体中细胞色素P450酶(CYP酶)和尿苷二磷酸葡萄糖醛酸转移酶(UGT酶)的代谢稳定性及性别差异。方法补骨脂酚分别与雄、雌性SD大鼠和男、女性人肝微粒体在37℃与不同辅酶因子孵育,应用高效液相色谱(HPLC)法测定补骨脂酚的剩余浓度,采用底物消除法观察补骨脂酚的代谢稳定性。结果补骨脂酚在雄、雌性SD大鼠肝微粒体中,CYP酶介导的Ⅰ相代谢固有清除率(Clint)分别是326.6±15.4和(77.2±4.8)mL·min~(-1)·kg~(-1),雄性代谢显著快于雌性(P<0.01);UGT酶介导的Ⅱ相代谢Clint分别是164.5±8.4和(419.1±24.1)mL·min~(-1)·kg~(-1),雌性代谢显著快于雄性(P<0.01);CYP酶和UGT酶共同代谢的Clint分别是1063.1±27.2和(781.2±16.5)mL·min~(-1)·kg~(-1),雄性代谢显著快于雌性(P<0.01)。在男、女性人肝微粒体中,CYP酶介导的Ⅰ相代谢Clint分别是24.8±2.1和(17.6±1.0)mL·min~(-1)·kg~(-1),男性代谢显著快于女性(P<0.01);UGT酶介导的Ⅱ相代谢Clint分别是176.4±26.5和(165.9±8.6)mL·min~(-1)·kg~(-1),代谢无显著性别差异;CYP酶和UGT酶共同代谢的Clint分别是262.5±20.9和(236.2±10.5)mL·min~(-1)·kg~(-1),代谢无显著性别差异。结论补骨脂酚在SD大鼠和人肝微粒体中,均发生CYP酶介导的Ⅰ相代谢和UGT酶介导的Ⅱ相代谢反应,且代谢稳定性具有一定的种属和性别差异。     

尿苷二磷酸葡萄糖醛酸转移酶基因多态性对药物代谢影响的研究进展

由尿苷二磷酸葡萄糖醛酸转移酶(UDP-glucuronosyltransferase,UGT)催化完成的葡萄糖醛酸结合反应是生物体内重要的Ⅱ相代谢途径,它与毒性或活性物质结合形成葡萄糖醛酸苷,将内源性、外源性化合物通过胆汁或肾脏排出体外。UGT是一个超家族酶,因主要利用UDP-尿苷二磷酸葡糖醛酸为糖基供体而得名。人类UCT广泛分布于体内的各种组织,包括肾、脑、皮肤、肠、脾、胸腺、心脏等,其中以     

布格呋喃与大鼠肝脏药物代谢酶的相互作用

目的：研究参与布格呋喃代谢的CYP450同工酶类型和体外代谢的酶促动力学特征,并观察口服布格呋喃对大鼠肝脏药物代谢酶的影响。方法：采用比色／动态荧法光及UV—HPLC法检测大鼠口服布格呋喃（8mg&#183;kg^-1&#183;d^-1,连续3日）后肝脏CYP450同工酶（CYP1A2、2C6、2C11、2D2、2E1和3A2）和Ⅱ相酶-谷胱甘肽巯基转移酶（GST）、尿苷二磷酸葡萄糖醛酸转移酶（UDPGT）和谷胱甘肽还原酶（GR）活性。应用肝微粒体温孵法测定布格呋喃体外代谢速率（Vmax和米氏常数Km）。比较布格呋喃在正常及高诱导大鼠肝微粒体中代谢速率的差异以及CYP1A2、2C6、2C11、2D2、2E1和3A2的选择l生抑制剂（呋拉茶碱、磺基苯吡唑、奥美拉唑、奎尼丁、戒酒硫和酮康唑）对布格呋喃代谢的抑制程度,鉴定参与布格呋喃代谢的CYP450同工酶类型。结果：布格呋喃在乙醇、地塞米松和3-甲基胆葸诱导大鼠肝微粒体中的Km、Vmax分别为正常组的11倍、6倍和1.3倍;应用CYP3A2、2E1和IA2的选择性抑制剂酮康唑、戒酒硫和呋拉茶碱可不同程度地抑制布格呋喃的代谢,使代谢速率下降为对照组的34％、47％和78％。     

食物,细胞色素P450酶与药物代谢

细胞色素Ｐ４５０系列酶对药物及外源性化合物的人体内代谢具有影响，有的可使之提高药效，减少毒副反应，有的可降低药效，增加毒性，甚至致癌。而食物可改变体内各种Ｐ４５０异检酶的含量和活性，因而可对药物代谢发挥间接作用。     

中药对药物代谢酶的影响

药物代谢酶在众多中西药物代谢中起着非常重要的作用.本文综述了近年来国内外学者就中药对药物代谢酶影响的研究思路、方法和进展.通过深入研究中药对药物代谢酶活性的影响,有利于中药基础理论的深入和发展;临床上应该重视中药与其他药物合用时所发生的代谢性相互作用,优化给药方案,从而提高临床用药的有效性和安全性.     

植物药及果蔬对药物代谢酶P450活性的影响

中草药及其他植物药在我国及东南亚国家应用广泛，在欧美也逐渐受到重视，一些中草药及植物药可能诱导或抑制肝脏细胞色素P450(CYP)药物代谢酶，从而引起自身及其他合用药物代谢的改变，因此可能导致药物不良反应和药物相互作用。     

细胞色素P450酶在药物代谢及开发研究中的应用

肝细胞色素Ｐ４５０酶技术在药物研究和筛选中的应用是创新药物开发研究的一个重要环节。本文综述了国外就肝Ｐ４５０酶应用于药物代谢研究及创新药物开发的现状,指出运用肝细胞色素Ｐ４５０酶技术筛选和开发研究创新药物是行之有效的。     

细胞色素P450酶系及其在药物代谢中的作用

综述了细胞色素P450酶系近年来的研究进展，对P450认识的不断深入，使人们有可能预测药物的相互作用和环境因素对药物代谢的影响     

Interethnic differences of drug-metabolizing enzymes

Polymorphisms exhibited by drug-metabolizing enzymes are well known and have been investigated for many years. Recently, the exploding field of pharmacogenetics has focused not only on the characterization of enzymes responsible for drug biotransformation but also, on describing the sources of variability in enzyme activity. While initial observations and studies focused on populations of Caucasian origin, reports for other populations followed. The incidence of a poor or slow metabolizer phenotype for a given enzyme caused by allelic variants may vary significantly between populations. The question arises as to whether a prediction of the phenotype (i.e. distribution and/or enzyme activity) can be accurately ascertained from genotype information gathered in a related population. This is exemplified by NAD(P):quinone oxidoreductase (NQO1) investigated in Canadian Native Indian (CNI), Inuit and Chinese populations and the cytochromes P4502C19 and 2D6. While the two North American Native populations are genetically distinct, they are both descendants from northern Asia. Consequently, one might suspect that on a pharmacogenetic basis, CNI and Inuit would be more comparable to Chinese as opposed to Caucasian populations. This is certainly not the case as demonstrated for all three enzymes. Also, for a reliable phenotype prediction, one needs to pay attention to ethnic "mixing" which occurs between certain populations. Ethnic diversity constitutes both a challenge and an opportunity to prudently apply pharmacogenetics so that variability in both drug disposition and effect may be better understood.     

Adjuvant-induced arthritis and drug-metabolizing enzymes

Rats given a single intradermal injection into the foot pad of 0.50 mg Mycobacterium butyricum, suspended in 0.1 ml of liquid paraffin, developed arthritis after a latent period of about 8 days. However, a decline in the activity of hepatic aminopyrine demethylase and the level of cytochrome P-450 occurred before the development of arthritis. Rats given the adjuvant preparation by the intraperitoneal route showed also a decreased activity of aminopyrine demethylase. An inverse correlation was found between the level of α₂-globulin and aminopyrine demethylase activity. Rats in which arthritis was induced by Mycoplasma arthritidus also showed a reduced activity of aminopyrine demethylase. The reduction of aminopyrine demethylase activity in adjuvant-treated rats was not caused by anorexia, neither could it be shown to be caused by a circulating hormonal factor. However, it was noted that the serum from many of the arthritic rats was greenish in colour and this might have been caused by the breakdown of certain haem compounds. The haem saturation of hepatic tryptophan oxidase was much less in adjuvant-induced arthritic rats than in controls. These results suggest a failure in haem biosynthesis and/or an accelerated breakdown of existing haem.     

Inducibility of rat brain drug-metabolizing enzymes

Cytochrome P450 from rat brain mitochondrial and microsomal fractions was found to be inducible by 3-methylcholanthrene, both in quantity of enzyme and in activity towards 7-ethoxyresorufin, which is a model substrate for the cytochrome P450 isoform specifically induced by 3-methylcholanthrene. Conversely, a phenobarbital treatment resulted in an induction of the microsomal cytochrome P450 only. On the other hand, the microsomal 1-naphthol-UDP-glucuronosyl transferase and epoxide hydrolase seemed to be non-inducible by 3-methylcholanthrene or by phenobarbital. The toxicological implications of these data are discussed.     

Cancer and phase II drug-metabolizing enzymes

Cancer development results from the interaction between genetic factors, the environment, and dietary factors have been identified as modulators of carcinogenesis process. The formation of DNA adducts is recognized as the initial step in chemical carcinogenesis. Accordingly, blocking DNA adducts formation would be the first line of defense against cancer caused by carcinogens. Glutathione-S-transferases inactivate chemical carcinogens into less toxic or inactive metabolite through reduction of DNA adducts formation. There are many different types of glutathione S-transferase isozymes. For example, GST delta serves as a marker for hepatotoxicity in rodent system, and also plays an important role in carcinogen detoxification. Therefore, inhibition of GST activity might potentiate the deleterious effects of many environmental toxicants and carcinogens. In addition, approximately half of the population lacks GST Mu expression. Epidemiological evidence showed that persons possessing this genotype are predisposed to a number of cancers including breast, prostate, liver and colon cancers. In addition, individual risk of cancer depends on the frequency of mutational events in target oncogenes and tumor suppressor genes which could lead to loss of chromosomal materials and tumor progression. The most frequent genetic alteration in a variety of human malignant tumors is the mutation of the coding sequence of the p53 tumor suppressor gene. O(6)-alkylguanine in DNA leads to very high rates of G:C deltaA:T transitions in p53 gene. These alterations will modulate the expression of p53 gene and consequently change DNA repair, cell division, and cell death by apoptosis. Also, changes in the expression of BcI-2 gene results in extended viability of cells by over-riding programmed cell death (apoptosis) induced under various conditions. The prolonged life-span increases the risk of acquiring genetic changes resulting in malignant transformation. In addition, a huge variety of food ingredients have been shown to affect cell proliferation rates. They, therefore, may either reduce or increase the risk of cancer development and progression. For example, it has been found that a high intake of dietary fat accelerates the development of breast cancer in animal models. Certain diets have been suggested to act as tumor promoters also in other types of cancer such as colon cancer, where high intake of fat and phosphate have been linked to colonic hyper-proliferation and colon cancer development. Different factors such as oncogenes, aromatic amines, alkylating agents, and diet have a significant role in cancer induction. Determination of glutathione S-transferase isozymes in plasma or serum could be used as a biomarker for cancer in different organs and could give an early detection.     

Immunomodulating agents and hepatic drug-metabolizing enzymes

Immunomodulating agents are increasingly used in clinical practice to alter the course of various malignancies, autoimmune diseases, or immunodeficiencies. Experimental data obtained in laboratory animals suggest that nearly all agents available today are likely to inhibit hepatic drug-metabolizing enzymes. Although further investigation is warranted, a direct stimulation of the reticuloendothelial system is likely to play a key role. Potentially severe drug interactions are the main clinical consequences to be considered, particularly in the field of cancer chemoimmunotherapy and vaccination. Besides immunomodulating agents, drugs with the toxic potential for immunoenhancement may also be considered in that respect.     

Effects of lignans on hepatic drug-metabolizing enzymes

The effects of lignans, related to macelignan, on hepatic microsomal drug-metabolizing enzyme (DME) activity were evaluated to elucidate the structure-activity relationship in mice and rats. The compounds carrying the methylenedioxyphenyl nucleus were found to be the most potent among compounds tested; which not only produced a marked inhibition of DME with a single dose but a significant induction with repeated treatments. Lack of the methylenedioxy group caused marked decrease in the activity, implying that a methylenedioxy group is essential and of major importance eliciting DME modifying activity. Part 15 in the series “Studies on crude drugs action on drug-metabolizing enzymes” For part 14, see ref 1.     

非甾体抗炎药药物代谢酶多态性的研究进展

非甾体抗炎药(NAIDs)是一类具有解热、镇痛和抗炎作用的药物,临床上用于治疗骨关节炎、类风湿关节炎等疾病,疗效确切但常伴有胃肠道不适等不良反应,其产生与其药物代谢酶的遗传多态性有关.参与NSAIDs氧化代谢的细胞色素P450酶系,主要有CYP2C9、CYP1A2、CYP2E1和CYP3A4,本文就NSAIDs的药物代谢酶及其多态性和P450代谢的部分NSAIDs(双氯芬酸、布洛芬、氟比洛芬、萘普生和醋氨芬)等作一综述.