ROLE OF HEPATIC FATTY ACID:COENZYME A LIGASES IN THE METABOLISM OF XENOBIOTIC CARBOXYLIC ACIDS

1. Formation of acyl-coenzymes (Co)A occurs as an obligatory step in the metabolism of a variety of endogenous substrates, including fatty acids. The reaction is catalysed by ATP-dependent acid:CoA ligases (EC 6.2.1.1-2.1.3; AMP forming), classified on the basis of their ability to conjugate saturated fatty acids of differing chain lengths, short (C₂-C₄), medium (C₄-C₁₂) and long (C₁₀-C₂₂). The enzymes are located in various cell compartments (cytosol, smooth endoplasmic reticulum, mitochondria and peroxisomes) and exhibit wide tissue distribution, with highest activity associated with liver and adipose tissue. 2. Formation of acyl-CoA is not unique to endogenous substrates, but also occurs as an obligatory step in the metabolism of some xenobiotic carboxylic acids. The mitochondrial medium-chain CoA ligase is principally associated with metabolism via amino acid conjugation and activates substrates such as benzoic and salicylic acids. Although amino acid conjugation was previously considered an a priori route of metabolism for xenobiotic-CoA, it is now recognized that these highly reactive and potentially toxic intermediates function as alternative substrates in pathways of intermediary metabolism, particularly those associated with lipid biosyntheses. 3. In addition to a role in fatty acid metabolism, the hepatic microsomal and peroxisomal long-chain-CoA-ligases have been implicated in the formation of the acyl-CoA thioesters of a variety of hypolipidaemic and peroxisome proliferating agents (e.g. cloflbric acid) and of the r (-)-enantiomers of the commonly used 2-arylpropionic acid non-steroidal anti-inflammatory drugs (e.g. ibuprofen). In vitro kinetic studies using rat hepatic microsomes and peroxisomes have alluded to the possibility of xenobiotic-CoA ligase multiplicity. Although cDNA encoding a long-chain ligase have been isolated from rat and human liver, there is currently no molecular evidence of multiple isoforms. The gene has been localized to chromosome 4 and homology searches have revealed a significant similarity with enzymes of the luciferase family. 4. Increasing recognition that formation of a CoA conjugate increases chemical reactivity of xenobiotic carboxylic acids has led to an awareness that the relative activity, substrate specificity and intracellular location of the xenobiotic-CoA ligases may explain differences in toxicity. 5. Continued characterization of the human xenobiotic-CoA ligases in terms of substrate/inhibitor profiles and regulation, will allow a greater understanding of the role of these enzymes in the metabolism of carboxylic acids.     

服用鱼油多不饱和脂肪酸对血液中脂肪酸组成的影响

高脂血症患者摄食含DHA33％、EPA10％的鱼油脂肪酸制剂,可增加全血脂肪酸组成中DHA的相对含量,降低EPA、AA的含量;可增加血小板膜脂肪组成中DHA、EPA的相对含量,增加DHA/AA、EPA/AA的比值;也可增加HDL_2、HDL_3的脂肪组成中EPA的相对含量。     

Decreased liver triglyceride content in adult rats exposed to protein restriction during gestation and lactation: Role of hepatic triglyceride utilization

We have previously demonstrated that protein restriction throughout gestation and lactation reduces liver triglyceride content in adult rat offspring. However, the mechanisms mediating the decrease in liver triglyceride content are not understood. The aim of the current study was to use a new group of pregnant animals and their offspring and determine the contribution of increased triglyceride utilization via the hepatic fatty‐acid oxidation and triglyceride secretory pathways to the reduction in liver triglyceride content. Pregnant Sprague–Dawley rats received either a control or a low protein diet throughout pregnancy and lactation. Pups were weaned onto laboratory chow on day 28 and killed on day 65. Liver triglyceride content was reduced in male, but not female, low‐protein offspring, both in the fed and fasted states. The reduction was accompanied by a trend towards higher liver carnitine palmitoyltransferase‐1a activity, suggesting increased fatty‐acid transport into the mitochondrial matrix. However, medium‐chain acyl coenzyme A dehydrogenase activity within the mitochondrial matrix, expression of nuclear peroxisome proliferator activated receptor‐α, and plasma levels of β‐hydroxybutyrate were similar between low protein and control offspring, indicating a lack of change in fatty‐acid oxidation. Hepatic triglyceride secretion, assessed by blocking peripheral triglyceride utilization and measuring serum triglyceride accumulation rate, and the activity of microsomal transfer protein, were similar between low protein and control offspring. Because enhanced triglyceride utilization is not a significant contributor, the decrease in liver triglyceride content in male low‐protein offspring is likely due to alterations in liver fatty‐acid transport or triglyceride biosynthesis.     

金牡蛎对大鼠高脂血症脂肪肝的防治作用

探讨金牡蛎、牛磺酸对肥胖性高脂血症脂肪肝的防治作用。金牡蛎和牛磺酸在适当减轻造模的物体重的同时,显著降低共血脂和肝组织脂肪含量,并显著改善肝组织病理学变化,结论：金牡蛎及其提取物牛磺酸可有效防治大鼠实验性高脂血症和脂肪肝。     

ROLE OF NON-ESTERIFIED FATTY ACIDS IN REGULATING PLASMA CHOLESTEROL TRANSPORT

1. The cholesteryl ester transfer protein (CETP) promotes an equimolar exchange of cholesteryl esters between the high density lipoproteins (HDL) and low density lipoproteins (LDL) in human plasma. 2. Sodium oleate converts this CETP-mediated process of exchange into one of net mass transfer of cholesteryl esters from HDL to LDL. 3. Thus, conditions which increase the concentration of non-esterified fatty acids in plasma may favour the redistribution of cholesterol from the non-atherogenic HDL to the atherogenic LDL fraction.     

EFFECT OF SALT LOADING ON BLOOD PRESSURE AND EICOSANOID METABOLISM OF SPONTANEOUSLY HYPERTENSIVE RATS FED A FISH OIL ENRICHED DIET

This study investigated the effects of dietary modification of prostaglandin (PG) synthesis on blood pressure regulation in spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats under conditions of normal and elevated salt intake. After an initial period of 4 weeks on either a 2-series PG 'inhibitory' diet of fish oil (maxEPA) or a control diet of saturated fat, half of each group received 1.5% saline for 1 week. Blood pressures were unaffected by diet during the period of normal salt intake, but following salt loading, the maxEPA-fed SHR showed a blood pressure increase (mean = 21 mmHg) relative to the EPA-fed rats on water. Rats on maxEPA showed impaired ability to generate serum thromboxane and diminished excretion of urinary 6-keto-PGF1 alpha and PGE2. SHR on water showed greater serum TXB2 generating capacity than WKY, but diminished urinary PGE2 excretion. Thus, the increased blood pressure observed in the salt-loaded SHR on the maxEPA diet may be explained by reduced renal PG synthesis resulting in either mild sodium retention and/or increased vascular reactivity.     

蛋黄磷脂中脂肪酸成分的GC／MS分析

超临界ＣＯ２萃取的蛋黄磷脂经甲基化处理，以薄层色谱鉴定后，用气相色谱－质谱技术及图谱检索，分析其脂肪酸组成和胆固醇，并求出７种脂肪酸的含量。     

PRIMARY ACTIVE TRANSPORT OF PROVASTATIN ACROSS THE LIVER CANALICULAR MEMBRANE IN NORMAL AND MUTANT EISAI HYPERBILIRUBINAEMIC RATS

We have previously demonstrated that the HMG-CoA reductase inhibitor pravastatin is efficiently taken up by the liver via the ‘multispecific anion transporter’ in an active manner.³ To further examine the fate of pravastatin within the liver, its biliary excretion was studied in a single-pass liver perfusion system and isolated liver canalicular membrane vesicles (CMVs) using normal (Sprague–Dawley rats; SDRs) and mutant Eisai hyperbilirubinaemic rats (EHBRs). In the liver perfusion experiments, the outflowing drug concentration reached a steady state at 30 min and the extraction ratio was approximately 0·7 in both rat strains. Both the steady state biliary excretion rate and bile flow rate of the EHBR group were 40% of those of SDRS. At steady state, the fraction of unchanged drug in bile was 25–34% in both groups. The concentration ratios of unbound drug in cytosol versus that in sinusoid and of that in bile versus that in cytosol were, respectively, 11 and 87 in SDRs, and 13 and 94 in EHBRs. After correction for the membrane potential (−40 mV in cytosol), the ratios became 49 and 19 in SDR and 58 and 21 in EHBRs, respectively. The finding that all of these values were much larger than unity suggested that active transport occurred from liver to bile, as well as from plasma to liver, in both rat strains. Furthermore, ATP-dependent uptake of pravastatin was clearly observed in CMVs prepared from EHBRs as well as SDRs, whereas the stimulation by ATP of DNP-SG transport in CMVs was observed only in SDRs. It was concluded that pravastatin is excreted into bile in high concentrations and a primary active transport mechanism which is maintained in EHBRs contributes to the biliary excretion of this drug.     

栉孔扇贝柱及扇贝边脂肪酸组成与含量

对山东烟台海洋养殖栉孔扇贝中的扇贝柱及扇贝边脂肪酸进行了比较研究。结果表明，扇贝柱和记忆吵饱和脂肪酸分别占脂肪酸总量的６５．０％和６６．２％，其中扇贝柱中高度不饱和脂肪酸为５５．１％，ＥＰＡ＋ＤＨＡ为３７．５％；扇贝边， 高度不饱和脂肪酸为４８．８％，ＥＰＡ－ＤＨＡ为２２．２％。     

毁损腹侧苍白球对大鼠觅药行为的影响

目的··:了解腹侧苍白球在药物强化中的作用。方法··:毁损依赖大鼠腹侧苍白球 ,利用条件性位置偏爱实验测定术前、术后依赖大鼠对注射吗啡侧的偏爱程度 ,评价腹侧苍白球在药物强化效应程度中的作用。结果··:依赖实验组大鼠术前在A侧停留的平均时间为806.5s±s27.4s ;术后在A侧停留的平均时间为594.7s±s30.2s ,依赖对照组A侧停留的平均时间为784.3s±s20.6s ,毁损腹侧苍白球明显减少依赖大鼠的位置偏爱行为。结论··:腹侧苍白球是调节强化作用的重要部位 ,伏隔核—腹侧苍白球通路是药物刺激和强化的共同通路     

24种海藻中脂肪酸含量的研究

用气相色谱法分析了２４种不同门类海藻脂肪的含量，结果表明，海藻脂肪酸以棕榈酸含量最高，约占总量的４０％，按分类比较，褐藻门海藻的脂肪酸总量及不饱和脂肪酸的含量都较高，而红藻门，绿藻门海藻的脂肪酸含量较低。     

褐藻胶对大鼠实验性肝纤维化的防治作用

褐藻胶是海藻的提取物，本文研究了四氯化碳诱导的大鼠肝纤维化模用褐藻胶后肝脏组织学和血清ＰＣⅢ和ＨＡ水平变化。结果表明，褐藻胶对实验性肝纤维化有一定的防治作用。     

盐酸三环哌酯在大鼠体内外的代谢

用大鼠原位灌流肝脏、整体实验和大鼠肝脏微粒体酶制备对盐酸三环哌酯(TCPN)的代谢转化进行了研究。结果经大鼠原位肝脏灌流后,灌流液经提取和HPLC分离制备,得到两个代谢产物。经MS,NMR,IR和UV鉴定,证明产物I是TCPN氮上脱甲基的产物,产物I是TCPN苯环羟化的产物。从大鼠igTCPN后的尿中及在TCPN和肝脏微粒体的温孵液中均得到产物I和产物II,提示TCPN的代谢转化主要由大鼠肝脏微粒体酶催化。以[³H]QNB为配体对TCPN及其代谢产物的受体结合活性进行了研究,结果表明产物I和产物I与M受体的亲和力分别是TCPN的1/20和1/50。     

年龄对大鼠肝脏生物转化功能及膜流动性的影响

通过与青年(3～4月)及中年(14月)组比较,研究了老年(24月)大鼠肝脏生物转化酶活性改变及膜流动性变化。结果表明,老年大鼠肝微粒体P-450含量、NADPH-细胞色素C还原酶活性无明显改变,但氨基比林N-脱甲基酶、苯胺羟化酶活性明显降低,且微粒体及胞浆GST、胞浆GSH-Px活性也明显下降;同时肝微粒体膜脂区流动性明显降低,膜Ch/PL值显著增大。研究提示,微粒体膜脂质环境及流动性变化与上述生物转化功能改变可能有一定的联系。     

THE INHIBITORY EFFECT OF BEVANTOLOL ON THE ACCUMULATION OF NON-ESTERIFIED FATTY ACIDS DURING ISCHAEMIA IN THE DOG HEART IN SITU

1. The left anterior descending coronary artery (LAD) was completely ligated for 90 min (i.e. myocardial ischaemia was produced) in the dog anaesthetized with pentobarbital. 2. Bevantolol, a beta 1-adrenoceptor antagonist, was injected (1 mg/kg, intravenously) 5 min before LAD occlusion. The bevantolol injection decreased heart rate without affecting blood pressure. 3. The myocardial samples were taken from the LAD area immediately after the end of LAD occlusion, and were subjected to analysis of the myocardial levels of non-esterified fatty acids (NEFA). 4. In dogs in which saline was injected, ischaemia produced accumulation of NEFA, especially arachidonic and palmitoleic acids, in the myocardium. 5. In dogs in which bevantolol was injected, the accumulation of NEFA induced by ischaemia was almost completely inhibited. 6. It is concluded that bevantolol inhibits ischaemia-induced accumulation of NEFA in the myocardium, and that stimulation of the beta 1-adrenoceptors is probably responsible for NEFA accumulation induced by ischaemia.