Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Formation of catecholestrogens (CE) by rat hepatic microsomes was re-examined because as recently shown; (1) CE formation can be catalyzed by an NADPH-dependent estrogen-4-hydroxylase (E-4-H(NADPH)) and by a peroxidatic, organic hydroperoxide-dependent estrogen-2/4-hydroxylase (E-2/4-H(OHP)), in addition to the established NADPH-dependent estrogen 2-hydroxylase (E-2-H(NADPH)); and (2) the indirect radiometric and the COMT-coupled radioenzymatic assays, used in many previous studies, may fail to provide an accurate measure, in particular, of 4-OH-CE. Using a direct product isolation assay, hepatic microsomes of both male and female rats were shown to express E-2/4-H(OHP) activity with properties similar to those of peroxidatic activity in other tissues. The activities of E-2/4-H(OHP) and E-2-H(NADPH) were affected differently by 5 out of 7 inducers of cytochromes P-450 administered in vivo. Phenobarbital and dexamethasone caused a 4- and 2-3-fold increase in E-2-H(NADPH) activity, respectively, but only a 38 and 20% increase in E-2/4-H(OHP) activity. Ketoconazol and beta-naphtoflavone caused a modest increase in E-2-H(NADPH) activity but a decrease in OHP-dependent activity. Clofibrate decreased peroxidatic activity by 50% and NADPH-dependent activity by approximately 20%. Both activities were increased by ethanol but decreased by isoniazide, an agent which induces the same form of cytochromes P-450 as ethanol. Polyclonal antibody against P-450p, a form of P-450 induced by glucocorticoids, inhibited E-2-H(NADPH) but not E-2/4-H(OHP) activity of untreated and of dexamethasone- and phenobarbital-treated rats. This study establishes that CE formation may occur in liver via the peroxidatic pathway and indicates that this pathway depends on forms of P-450 different from those mediating E-2-H(NADPH) activity. It also confirms and extends previous observations of the involvement of multiple, constitutive and induced forms of cytochrome P-450 in NADPH-dependent 2-hydroxylation in liver.
J Steroid Biochem Mol Biol 1990 Oct
PMID:Hepatic catecholestrogen synthases: differential effect of sex, inducers of cytochromes P-450 and of antibody to the glucocorticoid inducible cytochrome P-450 on NADPH-dependent estrogen-2-hydroxylase and on organic hydroperoxide-dependent estrogen-2/4-hydroxylase activity of rat hepatic microsomes. 217 38

Adult male mice of the NMRI strain were treated with a diet containing 0.5% clofibrate for 4 days to study its effects on peroxisomes, mitochondria, and lipid droplets in hepatocytes. Animals were also starved overnight to study the additional effects of starvation. Starvation of control animals had small effects on peroxisomes while the mitochondria became enlarged and occupied more of the cytoplasm. The number and fractional area of lipid droplets increased fivefold. Clofibrate treatment caused a doubling in number and average size of peroxisomes. No significant effects were observed in the number of mitochondrial profiles or lipid droplets although the size of the latter decreased to a third the value of the fed control. Starvation of clofibrate-treated animals led to a slight increase in the number of peroxisomes although their average size decreased by 30%. Mitochondrial average area increased and their fractional cytoplasmic area increased despite the decrease in numerical density. The number of lipid droplets increased twofold compared to that of clofibrate-treated animals while the size was not affected.
J Ultrastruct Mol Struct Res 1989 Apr
PMID:Effects of clofibrate treatment and of starvation on peroxisomes, mitochondria, and lipid droplets in mouse hepatocytes: a morphometric study. 262 78

The influence of clofibrate (ethyl-alpha-p-chlorophenoxy-isobutyrate), a hypolipidemic peroxisome proliferating agent, has been tested on the lungs of adult male rats. Drug administration for 7 days caused structural changes in two types of lung cells, both of which are involved in the metabolism of the pulmonary surfactant. By light microscopy the prominent features were the presence of enlarged type II alveolar epithelial cells and foamy intraalveolar macrophages. Compared with controls, type II cells in treated rats apparently contained more numerous surfactant-containing lamellar bodies, as visualized in semi-thin sections of Epon-embedded tissue. This difference was quantified morphometrically by light microscopy: the number of lamellar bodies was estimated as the profile number per individual type II alveolar cell, transsected at its nucleus. Clofibrate administration for 7 days resulted in a significant increase in the number of the lamellar inclusions. In contrast the number of type II alveolar cells per area of lung remained unchanged. There was no evidence of atelectasis or inflammatory infiltration in the drug-treated lungs, a finding confirmed in sections of perfusion-fixed, paraffin-embedded whole lung-lobes. By electron microscopy the lamellar inclusion bodies in the type II alveolar cells in treated rats, apart from being more numerous and sometimes smaller, were morphologically identical to those in controls. The vacuolated alveolar macrophages seen in treated rats also contained various lamellar phospholipid inclusions.(ABSTRACT TRUNCATED AT 250 WORDS)
Virchows Arch B Cell Pathol Incl Mol Pathol 1988
PMID:Modification of surfactant metabolizing cells in rat lung by clofibrate, a hypolipidemic peroxisome proliferating agent. Evidence to suggest that clofibrate influences pulmonary surfactant metabolism. 289 34

Recent investigations into the role of peroxisomes in mammalian lipid metabolism have employed double isotope methodologies to examine the influence of peroxisomal agents on lipid turnover in the liver and extra hepatic tissues of the living animal. The action of these agents, all of which caused extensive changes in the flux of lipid metabolism in the treated animals, may best be viewed in relation to their effects on the common pathway of fatty acid oxidation in peroxisomes. Clofibrate, for example, acts through induction of peroxisomal oxidases and catalase; glycolate and ethanol through activation of this pathway; and aminotriazole and allylisopropylacetamide through inhibition of the catalase step in the sequence. The data from these studies provide support for the concept of an important contributory and regulatory role of peroxisomes in relation to the overall balance of lipid metabolism, and emphasize that these organelles play a significant role in the oxidation of common fatty acids, as well as a potential for the elimination of fatty acids that are poorly oxidized by mitochondria. Additionally, the data raise intriguing questions on the extension of peroxisomal influence to include phospholipid metabolism and the substantial degree of inter-tissue communication which is involved in the balance of lipid metabolism in the whole animal.
Mol Cell Biochem 1984 Nov
PMID:On the role of peroxisomes in the metabolism of lipids--evidence from studies on mammalian tissues in vivo. 652 29

Peroxisomes were isolated from liver tissue of control and clofibrate-treated adult male NMRI mice and Sprague-Dawley rats. Phospholipids, cholesterol, triglycerides and free fatty acids were measured in the peroxisomes. The fatty acid profiles of the phosphatidylethanolamine, the phosphatidylcholine, the triglyceride and the free fatty acid fractions were also analyzed. Phosphatidylethanolamine was the dominating phospholipid in peroxisomes from untreated animals. The fatty acid profiles of phosphatidylethanolamine, free fatty acids and triglycerides were similar for untreated mice and rats but differences between the species were observed in the pattern derived from phosphatidylcholine. Phosphatidylcholine was the most abundant phospholipid after clofibrate treatment. Clofibrate treatment caused an increase in the concentrations of phospholipids and unsaturated long-chain fatty acids and a decrease in the concentrations of triglycerides, free fatty acids, cholesterol and shorter saturated fatty acids.
Comp Biochem Physiol B Biochem Mol Biol 1994 Dec
PMID:Lipid composition of liver peroxisomes isolated from untreated and clofibrate-treated mice and rats. 788 28

The aim of this work was to study in the adult rat heart the effect of modifications of fatty acid (FA) supply on the content of cytoplasmic fatty acid-binding protein (H-FABPc). To modify the amount of circulating lipids, three different treatments were chosen: (i) an hypolipidemic treatment with Clofibrate, administered daily through a gastric tube at a dose of 250 mg/kg per day for one week, (ii) a continuous intravenous infusion of 20% Intralipid, a fat emulsion, for one week at a dose of 96 ml/kg per day, and (iii) a normobaric hypoxia exposure (pO2 = 10%) for three weeks. At the end of each treatment plasma lipids, myocardial H-FABPc content and the activities of three key enzymes (citrate synthase, CS, fructose-6-phosphate kinase, FPK and hydroxy-acyl CoA-dehydrogenase, HAD) were assessed. With each of the three treatments a decrease of plasma cholesterol and phospholipid levels was observed. Plasma FA concentration increased with Intralipid infusion and decreased with chronic hypoxia. The heart H-FABPc content was increased by 20% with Clofibrate, decreased by 20% with chronic hypoxia and remained unaltered upon Intralipid treatment. The induced changes in H-FABPc content were not related directly to changes in plasma lipid levels. CS activity was slightly decreased in the hypoxia group, FPK activity decreased in the Clofibrate group, and HAD activity decreased in the Intralipid group. Among the various groups heart H-FABPc content was related to HAD activity. In conclusion, the H-FABPc content of adult rat heart appears responsive to changes in plasma lipid levels.
Mol Cell Biochem
PMID:Modulation of fatty acid-binding protein content of adult rat heart in response to chronic changes in plasma lipid levels. 823 51

Cinnarizine and flunarizine are piperazine derivatives with calcium antagonist and anticonvulsant properties and are used widely in the treatment of vertigo and circulatory disorders. They have been implicated recently in the aggravation, or even the induction, of parkinsonism in elderly patients. Because the aetiology of parkinsonism has been suggested as having a mitochondrial component, we have investigated the effects of both compounds on mitochondrial respiration and on the activities of the individual respiratory chain complexes. In intact mitochondria from rat liver, both drugs inhibited respiration rates, with substrates entering at Complex I (glutamate/malate) and Complex II (succinate). These effects could be explained by potent inhibitions (Ki 3-10 microM) of both complexes. Complex I is inhibited at a site near the ubiquinone-binding site, which is not competitive with respect to ubiquinone, whereas the inhibition of Complex II is apparently caused by competition with ubiquinone. Furthermore, the inhibition of NADH oxidation by flunarizine in submitochondrial particles caused an NADH-dependent generation of superoxide. These inhibitory properties of both compounds could be significant factors in the aggravation or induction of parkinsonism in elderly patients, in whom mitochondrial function already may be impaired.
Mol Pharmacol 1994 Jan
PMID:Flunarizine and cinnarizine inhibit mitochondrial complexes I and II: possible implication for parkinsonism. 830 75

Peroxisome proliferator-activated receptor alpha (PPAR alpha) mediates the effects of foreign chemical peroxisome proliferators on liver and kidney, including the induction of peroxisomal, mitochondrial, and microsomal enzymes involved in beta-oxidation of fatty acids. However, the role of this receptor in the peroxisome proliferative effects of the endogenous steroid dehydroepiandrosterone (DHEA) is not known. DHEA-3 beta-sulfate fd(DHEA-S) is shown to induce a liver peroxisome proliferative response in rats in vivo at a dose at which DHEA is much less active, which is consistent with cultured hepatocyte studies indicating a requirement for sulfation for the activation of DHEA. Transient transfection experiments demonstrated that in contrast to the prototypic foreign chemical peroxisome proliferator pirinixic acid, DHEA-S and its 17 beta-reduced metabolite, 5-androstene-3 beta, 17 beta-diol-3 beta-sulfate, are inactive in mediating trans-activation by PPAR alpha in COS-1 cells. Two other mammalian PPAR isoforms, gamma and delta/Nucl, were also inactive with respect to DHEA-S trans-activation. To test whether PPAR alpha mediates peroxisomal gene induction by DHEA-S in intact animals, we administered DHEA-S or clofibrate to mice lacking a functional PPAR alpha gene. Both peroxisome proliferators markedly increased hepatic expression of two microsomal cytochrome P450 4A proteins as well as six mRNAs known to be associated with the peroxisomal proliferative response in wild-type mice. In contrast, neither DHEA-S nor clofibrate induced these hepatic proteins and mRNAs in PPAR alpha-deficient mice. Clofibrate-induced expression of kidney CYP4A mRNAs was also blocked in the PPAR alpha gene knockout mice. Thus, despite its unresponsiveness to steroidal peroxisome proliferators in transfection assays, PPAR alpha is obligatory for DHEA-S-stimulated hepatic peroxisomal gene induction. DHEA-S, or one of its metabolites, may thus serve as an important endogenous regulator of liver peroxisomal enzyme expression via a PPAR alpha-mediated pathway.
Mol Pharmacol 1996 Jul
PMID:Peroxisome proliferator-activated receptor alpha required for gene induction by dehydroepiandrosterone-3 beta-sulfate. 870 Jan 21

Effects of cis-diamminedichloroplatinum (cisplatin) on rat kidney were investigated. Clinical parameters in rat urine and blood were studied. Blood urea nitrogen (BUN) and creatinine in blood and K+ in urine increased, but Na+ in urine decreased. Contents of total P450 and metabolic activities towards lauric acid and arachidonic acid in rat renal microsomes were not changed by cisplatin treatment. The levels of P450 isozymes (CYP4A1, 4A2, 4A8 and 2C23) were determined in rat renal microsomes by immunoblotting. The levels of CYP4A2 and 4A8 which are lauric acid omega-hydroxylases were not changed, but the levels of CYP2C23 and 4A1 were increased significantly by cisplatin treatment. Effects of clofibrate, a typical inducer for CYP4A1, on rat kidney were compared with those of cisplatin. Clofibrate induced palmitoyl CoA oxidase (a marker enzyme of peroxysome), CYP4A1, and CYP4A2 and reduced triglyceride level in plasma. Cisplatin had similar effects to clofibrate and induced peroxysomes as well as CYP4A1, although the effects were at a lesser extent than those of clofibrate. The induction levels of CYP4A1 correlated with increased levels of BUN. The present findings suggest that induction of P450 by cisplatin may take part in the renal injury or nephrotoxicity of cisplatin.
Res Commun Mol Pathol Pharmacol 1998 Jan
PMID:cis-Diamminedichloroplatinum induces peroxisomes as well as CYP4A1 in rat kidney. 952 52

The presence of cysteine and methionine groups together with an ability to bind long-chain fatty acid (LCFA) oxidation products makes liver fatty acid binding protein (L-FABP) an attractive candidate against hepatocellular oxidative stress. In this report, we show that pharmacological treatment directed at modulating L-FABP level affected hepatocellular oxidant status. L-FABP expressing 1548-hepatoma cells, treated with dexamethasone or clofibrate, decreased and increased intracellular L-FABP levels, respectively. Oxidative stress was induced by H2O2 incubation or hypoxia-reoxygenation. The fluorescent marker, dichlorofluorescein (DCF), was employed to measure intracellular reactive oxygen species (ROS). Hepatocellular damage was assessed by lactate dehydrogenase (LDH) level. Dexamethasone treatment resulted in a significant increase in DCF fluorescence with higher LDH release compared to control cells. Clofibrate treatment, however, resulted in a significant decrease in both parameters (p<0.05). Drug treatments did not affect cytosolic activities of glutathione peroxidase (GPx), superoxide dismutase (SOD), or catalase suggesting that the differences between treated and control cells may likely be associated with varying L-FABP levels. We conclude that L-FABP may act as an effective endogenous cytoprotectant against hepatocellular oxidative stress.
Mol Cell Biochem 2007 Jan
PMID:Role of cytosolic liver fatty acid binding protein in hepatocellular oxidative stress: effect of dexamethasone and clofibrate treatment. 1692 18


1 2 Next >>