镉、汞、铅在试管内对肝微粒体混合功能氧化酶活力和脂质过氧化作用的影响

本文研究了镉、汞、铅在试管内对肝微粒体混合功能氧化酶活力和脂质过氧化作用的影响。结果表明,这三种金属均直接抑制肝微粒体苯胺羟化酶活力,降低细胞色素P-450含量,增加无活性细胞色素P-420 含量,同时可使肝微粒体脂质过氧化作用加强,并都存在明显的剂量-反应关系。从而提示镉、汞、铅在试管内可能是通过激活膜脂质的过氧化使肝微粒体混合功能氧化酶活力降低。     

镉、铅、汞对苯巴比妥诱导肝微粒体药物代谢酶的影响

一次ip醋酸镉2.4mg/kg、醋酸铅100mg/kg或氯化汞 2.0 mg/kg均可抑制大鼠肝微粒体药物代谢酶。上述处理还可明显降低苯巴比妥对肝微粒’乙基吗啡N-脱甲基化酶、氨基比林N-脱甲基化酶、苯胺羟化酶和环己巴比妥羟化酶活力的诱导作用,降低苯巴比妥对细胞色素P450和细胞色素 b_5以及微粒体蛋白合成的诱导作用。结果提示镉、铅、汞可能通过降低微粒体酶的新生合成,抑制肝微粒体药物代谢酶。     

银杏内酯对结扎大鼠冠状动脉致心肌缺血的影响

目的:研究银杏内酯对大鼠心肌缺血的保护作用.方法:大鼠按体重分为7组,分别为银杏内酯10,20,40mg·kg-1组,银杏叶提取物150mg·kg-1组,普萘洛尔5mg·kg-1组,模型组和正常组.采用结扎冠状动脉左前降支造成心肌梗死模型,分别测定手术后各组大鼠的心肌损伤范围(坏死及缺血范围),血清磷酸肌酸激酶(CPK)、乳酸脱氢酶(LDH)活性及心肌组织中丙二醛(MDA)含量.结果:银杏内酯(10,20,40mg·kg-1)能明显减轻心肌损伤,降低心肌缺血大鼠血清中LDH和CPK活力及MDA含量.结论:银杏内酯对结扎大鼠冠状动脉所致心肌缺血损伤具有明显的保护作用.     

甘草酸二铵对大鼠心肌损伤的保护

目的：观察甘草酸二铵对大鼠急性心肌的缺血的保护作用。方法：利用异丙肾上腺素造成大鼠急性心肌缺血模型,观察甘草酸二铵对模型的心电图、心肌脂质过氧化物丙二醛（MDA）、超氧化物歧化酶（SOD）、血清磷酸肌酸激酶（CPK）减少,减少MDA的生成,增加心肌组织SOD的活力,抑制CPK和LDH的释放。结论：甘草酸二铵对大鼠心肌缺血有保护作用,机制可能与抗脂质对过氧化提高SOD活力有关。     

红花黄素对大鼠心肌缺血-再灌注模型的作用及机制研究

目的　研究红花黄素对心肌缺血 -再灌注大鼠的影响。方法　建立大鼠冠脉结扎致心肌缺血 -再灌注损伤模型 ,观察红花黄素预防性给药对缺血大鼠血浆中肌酸磷酸激酶 (CPK)、乳酸脱氢酶 (LDH)活性及心肌和血浆中脂质过氧化物丙二醛 (MDA)含量 ,超氧化物歧化酶 (SOD)活性的影响。结果　红花黄素预防性给药能明显降低血浆CPK、LDH的活性及MDA含量 ,提高SOD的活性 ,具有明显的抗氧化性。结论　红花黄素对实验性心肌缺血 -再灌注大鼠具有明显的保护作用 ,其作用可能与其抗氧化有关     

妊娠大鼠肝微粒体药物代谢酶活性

<正> 为了解妊娠时肝脏对外源性化合物的生物转化能力是否发生改变,本文以苯胺羟化酶(ANH)及氨基比林N-脱甲基酶(AMD)活性为代表,系统研究了妊娠大鼠肝微粒体实行芳香化及N-脱甲基化作用的变化趋向. 成年未孕及妊娠12～14 d(中孕)和18～20 d(晚孕)♀Sprague-Dawley大鼠,按文献制备肝微粒体,测定药物代谢酶活性.结果表明,未孕大鼠肝微粒体细胞色素P450含量,b_5含量及NADPH-细胞色素c还原酶     

延胡索乙素对大鼠实验性心肌缺血的保护作用

目的 研究延胡乙素（dl-THP)对大鼠实验性心肌缺血的保护作用。方法 观察dl-THP对垂体后叶素（pit)所致大鼠心电图急性缺血性改变的预防作用以及对异丙肾上腺素（Iso)引起心肌损伤大鼠的保护作用。结果 dl-THP对垂体后叶素所致心电图改变有明显预防作用。能对抗Iso所致ECG的ST段升高。显著抑制心肌组织中磷酸肌激酶（CPK）、乳酸脱氢酶（LDH）的释放,降低血清CPK和LDH水平,保护心肌组织超氧化物歧化酶（SOD）活性,减少丙二醛（MDA）生成。结论 dl-THP对实验性心肌缺血有明显的保护作用。     

川芎嗪抗大鼠心肌缺血及抗心肌细胞凋亡作用

目的研究川芎嗪对心肌缺血大鼠模型及心肌细胞凋亡的影响。方法建立大鼠心肌缺血模型,将24只大鼠按随机化原则分为对照组、高剂量组、低剂量组、假手术组。各组均测定心肌缺血和梗死范围以及CPK、LDH指标,并应用脱氧核糖核苷酸末端转移酶介导的缺口末端标记法（TUNEL法）测定各组心肌细胞凋亡及凋亡指数,比较各组间差异。结果高剂量组较对照组和低剂量组能明显降低心肌缺血大鼠模型的危险指数,降低心肌中CPK、LDH的升高。高剂量组能明显降低心肌细胞的凋亡指数,对心肌细胞凋亡的保护作用均明显高于生理盐水和低剂量组,与假手术组无统计学差异。结论川芎嗪对心肌缺血大鼠模型心肌梗死有明显保护作用,其作用机制可能与抗心肌细胞凋亡作用有关。     

保心康对异丙肾上腺素致大鼠心肌缺血的保护作用

目的观察保心康（BXK）对异丙肾上腺素（ISO）所致大鼠急性心肌缺血的保护作用。方法采用改良的Rona法复制大鼠急性心肌缺血模型,检测大鼠心电图（ECG）改变及血清中超氧化物歧化酶（SOD）活性、丙二醛（MDA）、乳酸（LD）、乳酸脱氢酶（LDH）以及肌酸磷酸激酶（CPK）含量,测定心肌含水量以及观察心肌组织病理改变。结果与心肌缺血模型组比较,BXK（18、36 mg·kg^-1）可显著改善心肌缺血大鼠心电图S-T段抬高,明显提高心肌缺血大鼠血清中SOD活性,降低MDA含量,降低LD,LDH和CPK含量。BXK（18、36 mg·kg^-1）能够不同程度减少心肌含水量及心肌缺血大鼠心肌组织病理损伤。结论保心康对大鼠急性心肌缺血模型具有明显的保护作用。     

新化合物TG6对心肌缺血/再灌注损伤的影响及机制研究

目的研究TG6对心肌缺血/再灌注损伤的保护作用及机制。方法采用整体大鼠心肌缺血/再灌注（I/R）实验,离体大鼠心脏低灌复灌实验和乳鼠心肌细胞缺氧/复氧损伤（H/R）实验等模型,以血清CK、LDH、T-SOD、MDA等为指标,研究TG6对心肌缺血再灌注损伤的保护作用。结果在整体大鼠心肌缺血再灌注损伤实验中,TG6显著减少I/R损伤后心肌梗死面积,减少血清中CK活力和MDA含量,减少LDH活力,增加T-SOD活力;在离体大鼠心脏低灌复灌实验中,TG6显著增加低灌复灌后心肌冠脉流量,减少心肌组织中MDA含量和CK、LDH外漏,提高心肌组织中T-SOD活力;在乳鼠心肌细胞H/R损伤实验中,TG6对正常生长条件下的细胞没有明显影响,提高Na2S2O4制备的心肌细胞H/R模型下细胞的存活率、降低细胞CK的释放率及细胞[Ca^2＋]i的含量。结论 TG6对心肌I/R损伤有一定的保护作用。     

Combined effect of nitrogen dioxide and cold stress on the activity of the hepatic cytochrome P-450 system in rats

The combined effects of nitrogen dioxide (NO2) and cold stress were assessed on the cytochrome P-450 system by measuring microsomal protein content, cytochrome P-450 content, aminopyrine N-demethylase activity, and aniline hydroxylase activity in the liver of male Wistar rats exposed to 4 ppm NO2 and/or cold environment (4 degrees C) for 24 h, 14 days, and 30 days. Exposure to cold alone changed the activity of the cytochrome P-450 system during the exposure up to 30 days, and exposure to NO2 alone also influenced it after 14 days and 30 days of exposure. Interactions were observed in the effect on the cytochrome P-450 system when rats were exposed to NO2 and cold simultaneously. There was a tendency that NO2 suppressed the increases in activities of the cytochrome P-450 system caused by cold of 24-h and 30-day exposure.     

Comparison of the form(s) of cytochrome P-450 induced by ethanol and glutethimide in cultured chick hepatocytes

In this study, using a combination of immunological and enzymatic characterizations, we compared the forms of cytochrome P-450 induced by ethanol and glutethimide in primary cultures of chicken embryo hepatocytes. Recently we purified a cytochrome P-450 of 50K molecular weight from chicken embryo liver using glutethimide as a prototypic inducer. Antibodies to both this chicken cytochrome P-450 and to rabbit cytochrome P-450 form 3a from the IIE subfamily detected microsomal proteins of 50K induced by either ethanol or glutethimide in cultured chick embryo hepatocytes, indicating the antigenic homology of these subfamilies of cytochromes P-450 among different animal species. However, the antibody to glutethimide-induced chick cytochrome P-450 of 50K inhibited p-nitrophenol hydroxylase and benzphetamine demethylase activities 85-90% in microsomes from both ethanol- and glutethimide-treated cells, indicating similar epitopes whose integrity is required for catalytic activity. In contrast, antibodies to rabbit cytochrome P-450 form 3a had little to no effect on these same microsomal activities. Both ethanol and glutethimide induced microsomal p-nitrophenol and aniline hydroxylase activities in cultured chick embryo hepatocytes. In microsomes from ethanol-treated cells, the turnover of p-nitrophenol per cytochrome P-450 was 2-fold greater than that induced by glutethimide treatment, suggesting that ethanol is inducing a form of cytochrome P-450 that has greater catalytic activity with this substrate than glutethimide-induced forms. Thus, in cultured chick embryo hepatocytes, ethanol may induce cytochromes P-450 from both the IIB and IIE subfamilies.     

Age-dependent toxicity of acorn extract in young and old male rats

Intraperitoneal administration of acorn extract of dosage levels of 200, 400 and 600 mg/kg body weight did not produce significant change in the hepatic microsomal cytochrome P-450 levels and the activities of NADPH-cytochrome c reductase, benzphetamine N-demethylase and aniline hydroxylase in young, adult rats (weighing 200-250 g), with the exception of the activity of benzphetamine N-demethylase at the 600 mg/kg dose which was decreased significantly. On the other hand, a dose of only 100 mg/kg body weight ip to old rats (weighing 400-450 g) caused significant decreases in the microsomal cytochrome P-450, benzphetamine N-demethylase and NADPH-cytochrome c reductase activities. However, there was no significant change in the activity of aniline hydroxylase in these rats, indicating selective inhibition of the microsomal enzymes and higher susceptibility of old rats than young ones to acorn toxicants. When the serum samples from the treated young rats were analyzed for sorbitol dehydrogenase (SDH), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities as markers of liver toxicity, these activities were significantly higher in the treated rats than the corresponding control values. Similar changes were noted for old rats receiving a dose of 100 mg/kg body weight of acorn extract. The results indicate that acorn extract affects old rats more than young rats as measured by its effect on liver and liver microsomal enzymes.     

Influence of drugs and chemical upon hepatic enzymes and proteins-I. Structure-activity relationship between various barbiturates and microsomal enzyme induction in rat liver.

The effect of phenobarbital, three N-phenylbarbiturates and three N-cyclohexylbarbiturates on microsomal protein content, cytochrome P-450, cytochrome b₅, aniline hydroxylase, aminopyrine demethylase, p-nitrophenol-glucuronyltransferase and the ultrastructure of hepatic cells in rat liver were studied to elucidate the influence of barbiturate structure on enzyme-inducing activity. Smooth endoplasmic reticulum increased after administration of phenobarbital, phetharbital or bucolome. Phenobarbital and phetharbital, especially phenobarbital, induced cytochrome P-450 and glucuronyl-transferase. On the other hand, the other barbiturates showed little enzyme-inducing activity. From these results, the type and spatial position of barbiturate substituents are considered important for hepatic microsomal enzyme induction. Aniline hydroxylase and aminopyrine demethylase activities changed coincidentally with cytochrome P-450 content in almost all rat livers. However, quantitative agreement of the changes in cytochrome P-450 content and drug-metabolizing activity could not be obtained, suggesting the possibility of substrate inhibition or of intrinsic inhibitors in the microsomal fraction. Bucolome, one of the N-cyclohexylbarbiturates, has been reported to be effective in the reduction of serum unconjugated bilirubin level in Gilbert's syndrome. However, in. spite of the increased smooth endoplasmic reticulum, there was a reduction in the microsomal protein content, cytochrome P-450 and glucuronyltransferase after bucolome administration. This would seem to indicate that the serum bilirubin-reducing mechanism of bucolome is different from that of phenobarbital and phetharbital.     

Effects of photoisomers of cyclodiene insecticides on liver and microsomal cytochrome P450 in rats

Threshold dosages of the photoisomers of cyclodiene insecticides, namely photochlordane, photodieldrin, and photoheptachlor, for the induction of hepatic microsomal cytochrome P450 (P450) and liver hypertrophy in male rats were at least one-quarter of those reported for corresponding parent cyclodienes. Maximum increase in total P450 concentration (30%) and demethylases activities (100%) was always respectively one-third or one-tenth of that reported for parent cyclodienes. The P450 isozymic form induced by photoheptachlor resembled that induced by pentobarbital (P4502B1) in its substrate specificity, spectral characteristics, and electrophoretic mobility. The induction of P450 was initially followed by hepatic hypertrophy. However, higher dosages of photoisomers caused wasting and lowered both the liver weight and the activity of aniline hydroxylase while those of mirex and endrin, which also caused wasting and lowered aniline hydroxylase activity, continued causing further hepatic hypertrophy.     

Studies on possible sulfadimethoxine toxicity to liver and liver drug metabolizing enzyme system of goats, quail and rats

No significant increases in serum SDH, ALT and AST activities were observed in goats and rats receiving oral sulfadimethoxine at 5 times the therapeutic dose. The quail showed significantly higher activities of SDH and ALT when compared to control values. Moderate increases in liver microsomal cytochrome P-450 and aniline hydroxylase activity were observed in goats and quail but no appreciable change in benzphetamine N-demethylase activity was detected in any species. These results suggest a lack of hepatic toxicity of sulfadimethoxine to these species under the reported experimental conditions.     

Lack of in vitro and in vitro effects of fenbendazole on phase I and phase II biotransformation enzymes in rats, mice and chickens.

Intraperitoneal administration of 10 mg fenbendazole/kg bw daily for 5 d caused no significant alterations in the activities of hepatic microsomal drug-metabolizing enzymes viz aminopyrine N-demethylase, aniline hydroxylase and cytosolic glutathione S-transferase in rats, mice and chickens. Similarly no significant difference in the amount of microsomal cytochrome P-450 and NADPH-cytochrome c reductase was found between control and treated animals. In vitro incubation of fenbendazole with rat, mouse and chicken microsomes suggests that the drug neither binds to microsomal protein cytochrome P-450 nor inhibits the activities of aminopyrine N-demethylase and aniline hydroxylase. Similarly in vitro addition of fenbendazole to cytosolic glutathione S-transferase from the above species did not alter the activity of this enzyme. The results indicate that fenbendazole does not alter the activity of hepatic microsomal monooxygenase system significantly in rats, mice and chickens at a dosage level of 10 mg/kg body weight. In vitro studies also indicate that fenbendazole does not interact with the hepatic microsomal monooxygenase system, indicating it is not a substrate for cytochrome P-450-dependent monooxygenase system.     

Altered activity of hepatic mixed-function mono-oxygenase enzymes in streptozotocin-induced diabetic rats.

1. In streptozotocin-induced diabetic male rats, hepatic microsomal aminopyrine N-demethylase activity was depressed, whereas aniline hydroxylase activity and cytochrome P-450 content were increased over control values. 2. In diabetic female rats, hepatic microsomal aminopyrine N-demethylase activity, aniline hydroxylase activity, biphenyl 4-hydroxylase activity, and cytochrome P-450 content were increased over control values. 3. Insulin treatment of diabetic male and female rats antagonized all physical and biochemical abnormalities of the diabetic state; 4. Methyl analogues of streptozotocin did not produce a diabetic state when injected into female rats, and resulted in no changes in aminopyrine N-demethylase activity, aniline hydroxylase activity, or cytochrome P-450 content. 5. Insulin treatment of non-diabetic female rats resulted in slight decreases in aminopyrine N-demethylase and aniline hydroxylase activities, but no changes in cytochrome P-450 content. These observations suggest that insulin primarily influences drug metabolism of diabetic animals through correction of the insulin-deficient diabetic state.     

Studies on the interaction of several boron hydrides with liver microsomal enzymes

The effects of several boron hydrides on hepatic microsomal enzymes isolated from adult male rats are described. Decaborane (B₁₀H₁₄) and the carboranes inhibited ethylmorphine N-demethylase and aniline hydroxylase activities in vitro. A decomposition product of decaborane also inhibited these microsomal enzyme systems. Pyridoxal phosphate, a coenzyme that alters the inhibitory actions of decaborane on certain enzyme systems, had no effect on the interaction of decaborane with these microsomal systems. Both decaborane and the carboranes are bound to cytochrome P-450; decaborane exhibited a modified type II spectral change, whereas o- and m-carborane exhibited type I spectral changes. Although a slight increase in aniline hydroxylase activity occurred, ethylmorphine N-demethylase activity and cytochrome P-450 content were not significantly changed when decaborane was administered daily for 3 days at doses of 5 mg/kg or 12 mg/kg. Similarly, the activity of these microsomal systems was unaltered after a single dose (12 mg/kg) of decaborane. During these studies morphologic changes of liver tissue occurred, confirming previous studies by other investigators that the liver is a site of pathology caused by decaborane. The potential utility of decaborane and other boron hydrides as pharmacologic tools in investigating hepatic microsomal drug metabolism is discussed.     

Prevention of acetaminophen-induced hepatotoxicity by dimethyl sulfoxide

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.