Serum zinc and serum copper and indices of drug metabolism in alcoholics

Summary Serum zinc and copper levels were studied in relation to in vitro and in vivo drug metabolism in 25 alcoholics, in whom various diseases of the liver had been diagnosed by histology. Serum zinc was elevated in alcoholics with normal or fatty liver and was low in those with alcoholic hepatitis or cirrhosis. There was a significant positive correlation between serum zinc and cytochrome P-450 content of liver biopsies. The relationship between zinc and antipyrine half-life was significant and non-linear. Serum copper level was elevated in all the alcoholics and no significant relationship could be found between copper and drug metabolism in alcoholics. The findings suggest parallelism between changes in serum zinc and indices of drug metabolism in alcoholics.     

Hepatic injury and drug metabolism in patients with alpha-methyldopa-induced liver damage

Summary The clinical picture and drug metabolism in 36 consecutive patients with alpha-methyldopa — induced hepatic injury were investigated. The diagnosis was based on case history and biochemical, histological and follow-up studies after withdrawal the drug. Alpha-methyldopa-induced liver damage was found to occur in two phases, acutely within months and chronically within years after beginning treatment. Differences were also found in clinical symptoms and the results of liver tests on the patients if they were divided on the basis of the time factor. Drug metabolism was impaired in patients with alpha-methyldopa-induced liver damage, as indicated by low cytochrome P-450 level in liver biopsies and prolonged antipyrine elimination rate from plasma. Disappearance of the symptoms and normalisation of the liver tests after drug withdrawal occurred faster in patients with an acute type of hepatotoxicity than in subjects with delayed onset of the symptoms. The occurrence of hepatotoxicity in four members of a family suggests a genetic disposition to alpha-methyldopa-induced hepatic injury. The occurrence of two phases of liver damage suggests that a possible mechanism for acute hepatotoxicity might be an allergic reaction to metabolic intermediates produced during breakdown of alpha-methyldopa in the liver. For cases of delayed onset the cause might be increasing damage to microsomal liver protein due to covalent binding during long-term exposure to the drug.     

Liver size and indices of drug metabolism in alcoholics

Summary The role of liver size in drug metabolism was investigated in 34 chronic alcoholics and 28 controls by comparing antipyrine half-life with biopsy content and total amount of hepatic cytochrome P-450 (P-450) and liver weight. Liver size was significantly greater in alcoholics than in controls. Total P-450 was increased and antipyrine metabolism was enhanced in alcoholics with normal histology of the liver. In subjects with alcoholic hepatitis or cirrhosis, the antipyrine half-life was prolonged and P-450 was decreased. Alcoholics with fatty liver had a reduced P-450 content, but the total amount of P-450 and the antipyrine half-life were normal. The results demonstrate in alcoholics that an enlarged liver of normal histological appearance is associated with enhanced drug metabolism. In subjects with fatty liver the drug metabolizing capacity per unit weight of liver is often impaired, but the increase in liver size leads to undisturbed total oxidizing capacity and normal in vivo metabolism. In alcoholic hepatitis drug metabolism is impaired in spite of hepatomegaly. In cirrhosis the enlargement of the liver appears to compensate for the decreased P-450 content resulting in only slightly decreased total P-450, and the severely impaired in vivo drug metabolism may be due to derangement of blood flow.     

Hepatic blood flow and drug metabolism in patients on enzyme-inducing anticonvulsants

Summary Liver blood flow and indices of hepatic drug metabolism (antipyrine elimination rate and cytochrome P-450 concentration in liver biopsy specimens) were studied in 19 epileptics on long-term anticonvulsant treatment, and in 18 controls. The size of the liver and the total estimated liver blood flow were greater in the epileptics than in the controls, whereas the relative liver blood flow (per unit weight of the liver) was not significantly different. The epileptics had higher cytochrome P-450 levels and they eliminated antipyrine faster than the controls. It was concluded that long-term ingestion of enzyme-inducing anticonvulsants is associated with an increase in the total hepatic blood flow in parallel with the increase in liver size, and not as an independent phenomenon. Since the relative perfusion rate of the hepatocytes was unchanged, the enhanced activity of drug metabolizing enzymes is presumed to be mainly responsible for the increased drug clearance observed in epileptic subjects.     

人肝微粒体中尼莫地平代谢的酶动力学及其抑制(英文)

目的:在体外研究人肝微粒体中尼莫地平代谢的酶动力学及选择性的细胞色素P-450(CYP450)酶抑制剂对尼莫地平代谢的影响。方法:采用人肝微粒体研究尼莫地平脱氢酶的代谢动力学,运用Eadie-Hof-stee方程估算其动力学参数。在体外运用CYP450酶的选择性抑制剂探讨其对尼莫地平代谢的影响及人肝微粒体中参与尼莫地平二氢吡啶环脱氢代谢的CYP450酶。结果:尼莫地平在人肝微粒体中的代谢存在较大的个体差异,尼莫地平脱氢酶的K_m为(36±11)μmol,其V_m为(17±7)μmol·g~(-1)·min~(-1)。酮康唑和三乙酰竹桃霉素竞争性地抑制尼莫地平二氢吡啶环脱氢代谢,其K_i值分别为0.59和122.2μmol。非那西丁、奎尼丁、DDC、Sul和Tra对尼莫地平二氢吡啶环脱氢代谢没有明显的影响。结论:尼莫地平在体内的药物动力学个体差异与其在肝中的代谢存在多态性有关。CYP3A参与了尼莫地平二氢吡啶环脱氢代谢,CYP3A的抑制剂可能会与尼莫地平发生代谢相互作用。     

Relationship between lipid composition and drug metabolizing capacity of human liver

Summary The relationship between hepatic glycerolipids and microsomal drug-metabolizing enzymes was studied in liver biopsies from 41 subjects. The series included obese, diabetic, epileptic and chronic alcoholic patients, all of whom were hospitalized for suspected hepatic ailments (fatty liver, hepatitis or cirrhosis). Therapy with enzyme-inducing anticonvulsants was associated with high phospholipid and cytochrome P-450 and low triacylglycerol concentration in the liver. In patients with fatty liver or cirrhosis low phospholipid and cytochrome P-450 and high triacylglycerol concentrations were observed. There was a significant correlation (r (Pearsons's product moment correlation coefficient) =0.91) between the hepatic phospholipid and cytochrome P-450 concentration. The cytochrome P-450 concentration was inversely related (r=–0.74) to the triacylglycerol concentration. The positive correlation between hepatic phospholipids and drug-metabolizing enzymes could be interpreted as indicating that in human liver phospholipid and cytochrome P-450 synthesis share common regulators, or that phospholipids are necessary for the maximum rate of cytochrome P-450 synthesis.     

Measurement of hepatic drug-metabolizing enzyme activity in man

Summary Three parameters of hepatic drug metabolism, cytochrome P-450 (P-450) content, antipyrine metabolism and urinary excretion of glucaric acid (GA) were investigated in 161 patients who underwent diagnostic liver needle biopsy. P-450 and antipyrine metabolism, but not GA were related to histological changes in liver. All the parameters were significantly increased in subjects treated with enzyme-inducing drugs, the extent of induction being related to alterations in liver histology. The largest responses were seen in subjects with an intact liver and the smallest in those with hepatitis or cirrhosis. Therapy with inducers partly compensated for the impairement in drug metabolism caused by the disease process; thus, some patients with altered liver had normal values in the tests if they had been treated with inducers. There were significant correlations between in vivo and in vitro parameters of drug metabolism, but in the interpretation of data selection of the material and the parameters influenced the results. Thus, the antipyrine plasma clearance rate was directly related to P-450 and GA values, whereas the correlation between the latter and the drug half-life was non-linear. Also, comparison of selected groups of patients resulted in better correlations between the indices of drug metabolism than in the entire series. The results demonstrate that the overall picture of hepatic drug metabolism in man is largely determined by histological changes in the liver and by exposure to drugs, which are reflected differently in various assays of hepatic drug metabolism. Quantitative evaluation of these factors, and selection of the appropriate assay method, seem to be of importance in investigating hepatic drug metabolism in man.     

Comparison of trimethadione and antipyrine as indicators of oxidative drug metabolizing capacity in man

Summary Ten healthy male volunteers were given trimethadione (TMO) 4 mg/kg and antipyrine (AP) 500 mg alone or concomitantly to determine whether the metabolism of the drugs was mediated by the same or closely related forms of cytochrome P-450.Whether administered alone or together the clearance (CL) and half-life (t_1/2) of TMO and AP were the same, and there was a good correlation between the CL and t_1/2 of TMO and AP (aloner=0.755 and 0.623, respectively; coadministeredr=0.771 and 0.503, respectively). Excretion of AP and its main metabolite and the clearance for production of AP metabolites after AP was administered alone were not significantly different when TMO and AP were taken together.When the two drugs were administered alone or coadministered, the correlation between the CL of TMO and the excretion of 3-hydroxymethyl-3-norantipyrine (NORA) was close (aloner=0.734, coadministeredr=0.749). The correlation between the CL of TMO and CLm of NORA when TMO and AP were given alone or concomitantly was 0.762 and 0.772, respectively.The findings suggest that TMO metabolism and the formation of NORA in healthy subjects are mediated by a closely related form(s) of the cytochrome P-450 system.     

Endotoxin depresses hepatic cytochrome P450-mediated drug metabolism in women

Aims In men, the inflammatory response to intravenous endotoxin depresses apparent oral clearances of antipyrine, hexobarbitone, and theophylline. The aim of this study was to investigate whether there might be gender differences in the regulation of hepatic cytochromes P450.
Methods Experiments were carried out in seven healthy women volunteers (ages 19–51, median 22 years). Each woman received a cocktail of the three drugs on two occassions, once after a saline injection and again after endotoxin.
Results Endotoxin injections, but not saline, caused the expected physiologic responses of inflammation including fever and increases in circulating tumor necrosis factor-α, interleukin-6, and C-reactive protein. When compared with the saline control studies, endotoxin significantly decreased clearances of all probes: antipyrine, 31% (95%CI 21%–41%); hexobarbitone, 20% (95%CI 10–31%); and theophylline, 20% (95%CI 10%–30%). The decreases were comparable with those found in the men previously studied (35%, 27%, and 22%, respectively).
Conclusions These data show that endotoxin-induced inflammation decreases hepatic cytochrome P450-mediated metabolism of selected probe drugs in women as it does in men.     

Induction of drug metabolizing enzyme system in the liver

Summary 1. Accelerated drug metabolism in liver cells was discovered during studies of the cause of barbiturate tolerance and of the way in which polycyclic hydrocarbons protect against the actions of several carcinogenic compounds. — 2. It is elicited by many lipid soluble drugs and is accompanied by increased synthesis of haem and enzyme proteins. It is due to increased activity of the drug metabolizing microsomal enzyme-complexes in the liver which consist of non specific mixed function oxidases and various transferases. — 3. Acceleration of drug metabolism is accompanied by hypertrophy of smooth intracellular membranes and enlargement of the liver. It is dependent on the concentration of the inducer in the endoplasmic reticulum and seems to be influenced by the stability of a complex formed between the drug and cytochrome P-450, as well as by certain, as yet unidentified properties possessed by certain types of inducing agents. — 4. In man it has been observed in patients during and after treatment with a few drugs which have a high inducing capacity and are prescribed in large doses. — 5. Accelerated drug metabolism might be highly advantageous and beneficial in protecting an organism against an overload of endogenous or exogenous toxic compounds, but it can also be harmful if it results in increased production of toxic metabolites. — 6. It can be regarded as a hitherto unknown pharmacological effect on the regulation of the synthesis-rate of enzymes involved in drug metabolism.Presented as Feldberg Foundation Lecture 1972 in St. Mary's Hospital Medical School on March 8th, 1972     

细胞色素P450与药物代谢的研究现状

细胞色素P450(CYP)在众多中西药物代谢中起着非常重要的作用。本文综述了与药物代谢相关的CYP亚型、CYP与药物相互作用的关系及中药对CYP的影响，旨在合理解释和预测临床上药物间相互作用和药物不良反应等。同时选择适当的药物作为探针来评价CYP的活性，为实现临床个体化给药提供科学依据。     

2，4，5－三氯苯胺体外代谢生成一氧化碳的途径与三卤苯胺的构效关系研究

实验证明，２，４，５－三氯苯胺（ＴＦＡ）与大鼠肝微粒体、ＮＡＤＰＨ和分子氧共存时可经历脱氟、对位羟化和氧化释放一氧化碳（ＣＯ）等代谢过程。与对照组（Ｃｏｎｔｒｏｌ）微粒体相比，苯巴比妥（ＰＢ）或地塞米松（ＤＥＸ）诱导的微粒体，使２，４，５－ＴＦＡ代谢降解为ＣＯ的速度分别提高３～８倍，脱氟速度提高１～４倍，对位羟化速度提高１．９～１．５倍，底物消失速度提高２～２．５倍。而２，４，６－ＴＦＡ，２，４，５－与２，４，６－三氯苯胺（ＴＣＡ）和１，２，４－三氟苯（ＴＦＢ）等经一般代谢几乎不产生ＣＯ，ＰＢ或ＤＥＸ诱导的微粒体使其转化为ＣＯ的能力也低至可忽略不计。同时，在Ｃｏｎｔｒｏｌ或ＰＢ微粒体中，２，４，５－ＴＦＡ的底物消失与脱氟两种速度比平均约为１：１，在ＤＥＸ微粒体中，两种速度比则为１：２，而２，４，６－ＴＦＡ在ＰＢ微粒体中的两种速度比为１：０．６。两个ＴＦＡ的对位羟化速度相对较慢，而两个ＴＣＡ几乎不能进行对位羟化。     

地尔硫抑制大鼠肝脏药物代谢的机制

目的:研究地尔硫(艹卓)(DZ)抑制大鼠肝脏药物代谢的机制.方法:(1)SD大鼠未诱导或经地塞米松(DEX)、苯巴比妥(PB)、β萘黄酮(BNF)诱导,制备肝微粒体,于DZ体外37℃温孵25min,检测细胞色素P450-Fe(Ⅱ)-代谢物(MI)复合物.(2)未诱导大鼠ip DZ 100mg/kg 3d,或经DEX诱导再给予单剂量DZ 100mg/kg,制备肝微粒体并检测MI复合物.结果:DEX、PB诱导组在体外分别有30.62%和10.30%MI复合物形成.未诱导大鼠ip DZ 3d,体内检测到7.9%MI复合物;经DEX诱导再给予单剂量DZ的大鼠,体内有17.57%MI复合物形成.结论:DZ在大鼠肝脏中经细胞色素P450 3A催化,发生N-去甲基化,生成的活性代谢物可与P450 3A络合而形成MI复合物,使P450 3A丧失部分活性.     

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。     

细胞色素P450的基因多态性与药物代谢

细胞色素P450（cytochrome P450，CYP）是重要的药物代谢酶，参与催化多种内源和外源化合物，特别是多种临床药物的生物转化。CYP存在广泛的基因多态性和表型多态性，使其对于各种化合物的代谢存在统计学个体差异。核受体是配体依赖性转录因子超家族，与药物代谢过程中的基因表达调控密切相关，被外源物质活化后诱导或抑制CYP基因的表达。现综述CYP与药物代谢、CYP的基因多态性、CYP表达的诱导机制、核受体及其配体诱导CYP表达及近年研究CYP450的各种实验方法。     

Cytochrome P-450 and Drug-induced Spectral Interactions in the Hepatic Microsomes of Trout,Salmo trutta lacustris*

Abstract The properties of various components of a drug-oxidizing mono-oxygenase system in the liver of trout (Salmo trutta lacustris) were studied. The concentration of the cytochrome P-450 was about 7 nmol/g liver wet weight when measured in the 12,000 × g supernatant and 0.2 nmol/mg protein when measured in the “microsomal” fraction. The activity of NADPH-cytochrome c reductase was about 2000 nmol cyt. c reduced/g liver/min. measured in the homogenate and 20 nmol/mg protein/min. when measured in the “microsomal” fraction. The distribution of the cytochrome P-450 into different centrifugal fractions indicates that it is localized in the endoplasmic reticulum. The cytochrome P-450 present in the fish liver microsomal fraction was capable of interacting with different substances resulting in type II (aniline, n-octylamine, cyanide) and a reversed type I (n-butanol) spectra. Substances producing type I spectra in the rat liver microsomes, did not give any spectra (hexobarbital, SKF 525A) or gave unclassified spectral changes with the fish liver cytochrome P-450 (bromobenzene, DDT, piperonyl butoxide). Spectral dissociation constants were calculated for aniline and n-octylamine. Further experiments indicated that the mono-oxygenase system in the trout liver microsomes can metabolize aminopyrine, aldrin and 3,4-benzpyrene.     

西尼地平在人肝微粒体内代谢及代谢抑制

目的：在体外研究西尼地平在人肝微粒体内的代谢及选择性细胞色素P-450（CYP450）酶抑制剂对其代谢的影响。方法：在体外用人肝微粒体研究西尼地平的代谢,并用CYP450酶的选择性抑制剂探讨其对西尼地平代谢的影响及人肝微粒体中参与西尼地平二氢吡啶环脱氢代谢的CYP450酶。结果：西尼地平在人肝微粒体内被迅速代谢物M1,二氢吡啶环侧链脱甲基代谢物M2,二氢吡嘧环脱氢及其侧链脱甲基代谢物M3,酮康唑竞争性地抑制西尼地平二氢吡啶环的脱氢代谢,同时降低西尼地平的代谢速率,而其它抑制剂,奎尼丁,α-Naphthoflavone,diethyldithiocarbamate,sulfaphenazole和tra-nylcypromine对西尼地平二氢吡啶环的脱氢代谢没有明显的影响。结论：西尼地平在人肝微粒体内被迅速代谢,其二氢吡啶环的脱氢代谢是其代谢的关键性的步骤,CYP3A作为主要的CYP酶参与了西尼地平二氢吡啶环的脱氢代谢,CYP3A的抑制剂可能会与西尼地平发生代谢相互作用。     

Effect of cimetidine on microsomal drug metabolism in man

Summary The effect of cimetidine on human microsomal drug metabolism was studied. In five of six healthy volunteers therapeutic doses of cimetidine prolonged the half-life of antipyrine (range 12–37%; p<0.05). Its clearance was decreased in five subjects (range 2–18%) and was increased in one subject (15%), the changes not being statistically significant. The volume of distribution increased on average by about 14% (range 9–19%; p<0.001). Cimetidine in vitro inhibited the hydroxylation of benzo(a)pyrene and coumarin, as well as the O-deethylation of 7-ethoxycoumarin, by homogenised liver biopsies. The in vitro studies suggest that the effect of cimetidine on antipyrine elimination is due to inhibition of microsomal drug metabolism, which may prove an important drug interaction.Part of this work was presented at the Fall Meeting of the German Pharmacological Society, Munich, September 1979 (Puurunen et al. 1979)     

中国人肝微粒体中细胞色素P450酶含量和活性的个体间差异(英文)

目的:比较不同中国人肝微粒体中几种重要细胞色素P450(CYP)的酶含量和活性。方法:运用West-ern斑点分析和光密度扫描,对17个汉族、17个壮族和8个苗族受试者肝微粒体中的细胞色素P4501A2(CYP1A2)、2C9及3A4进行定量;非那西丁、甲磺丁脲、异喹胍和奥美拉唑分别用于体外测量CYP1A2、2C9、2D6及3A4的活性。结果:CYP1A2、2C9及3A4的含量和活性具有很大的个体间变异,另外CYP2D6的活性在各样本间也有很大差异;CYP3A4(32％)是中国人肝微粒体中含量最丰富的CYP,CYP2C9(19％)和CYP1A2(16％)的含量也很可观;除了CYP1A2的含量和活性具有一定的种族和性别差异外,未发现其它CYP具有种族和性别差异;CYP1A2、2C9和3A4的酶蛋白含量分别和它们的活性具有很好的相关性。结论:我们的结果为在中国人中进行药物代谢研究提供了非常有价值的信息。     

Differential induction of antipyrine metabolism by rifampicin

Summary Antipyrine is oxidised to three main metabolites in man. There is evidence that the different metabolites are products of different forms of cytochrome P-450. The effect of rifampicin administration for two weeks on the rates of formation of these metabolites was investigated in healthy volunteers. Rifampicin increased antipyrine clearance and shortened its half-life. Two weeks after stopping rifampicin the induction had largely been reversed. Clearance to all three metabolites was increased by rifampicin. Clearance to 3-hydroxymethylantipyrine was increased from 7.8±0.9 ml/min to 13.3±1.3 ml/min, to norphenazone from 5.8±0.6 ml/min to 19.3±2.1 ml/min and to 4-hydroxyantipyrine from 14.3±2.2 ml/min to 21.9±3.9 ml/min. Thus clearance to norphenazone was increased to a much greater extent than to either of the other two metabolites. It is concluded that this provides evidence for the involvement of at least two different forms of cytochrome P-450 in antipyrine metabolism in man.