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Effects of clofibrate on the metabolism of progesterone and oestradiol in rat liver microsomal fraction.

ABSTRACT: 1. The substrate conversion of [4-(14)C]progesterone and [4-(14)C]oestradiol during incubation with the liver microsomal fraction from both control and clofibrate-treated rats amounted to about 10-15 and 20-25% respectively. 2. The metabolites of progesterone formed by preparations from control rats were hydroxylated in the 16alpha-position (14%), the 6beta-position (12%) and the 2alpha-position (7%). Of the products formed from oestradiol 12% were recovered as a 16alpha-hydroxylated derivative whereas 5% had a 6beta- and 2% a 6alpha-hydroxyl group. 3. Clofibrate affected the microsomal metabolism of both progesterone and oestradiol. It induced 7alpha-hydroxylation of both compounds, metabolic conversions not found in control rats. The 6beta-hydroxylation of progesterone and the 6alpha-hydroxylation of oestradiol were enhanced by a factor of 2 and 3.5 respectively. The 2alpha-hydroxylation, and the 20alpha- and 20beta-hydroxy steroid reduction of progesterone were significantly decreased as were the 16alpha- and the 6beta-hydroxylation of oestradiol.

SUBMITTER: Einarsson K

PROVIDER: S-EPMC1165997 | biostudies-other | 1973 Nov

REPOSITORIES: biostudies-other

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Effects of clofibrate on some microsomal hydroxylations involved in the formation and metabolism of bile acids in rat liver.

Project description:1. The liver microsomal metabolism of [4-14C]cholesterol, endogenous cholesterol, 7 alpha-hydroxy-4-[6 beta-3H]cholesten-3-one, 5-beta-[7 beta-3H]cholestane-3 alpha, 7 alpha-diol and [3H]lithocholic acid was studdied in control and clofibrate (ethyl p-chlorophenoxyisobutyrate)-treated rats. 2. The extent of 7 alpha-hydroxylation of exogenous [414C]cholesterol and endogenous cholesterol, the latter determined with a mass fragmentographic technique, was the same in the two groups of rats. The extent of 12 alpha-hydroxylation of 7 alpha-hydroxy-4-cholesten-3-one and 5 beta-cholestane-3 alpha, 7 alpha-diol was increased by about 60 and 120% respectively by clofibrate treatment. The 26-hydroxylation of 5 beta-cholestane-3 alpha, 7 alpha-diol was not significantly affected by clofibrate. The 6 beta-hydroxylation of lithocholic acid was about 80% higher in the clofibrate-treated animals than in the controls. 3. The results are discussed in the context of present knowledge about the liver microsomal hydroxylating system and bile acid formation in patients with hypercholesterolaemia, treated with clofibrate.

| S-EPMC1163766 | biostudies-other

Purification of phospholipid methyltransferase from rat liver microsomal fraction.

Project description:Phospholipid methyltransferase, the enzyme that converts phosphatidylethanolamine into phosphatidylcholine with S-adenosyl-L-methionine as the methyl donor, was purified to apparent homogeneity from rat liver microsomal fraction. When analysed by SDS/polyacrylamide-gel electrophoresis only one protein, with molecular mass about 50 kDa, is detected. This protein could be phosphorylated at a single site by incubation with [alpha-32P]ATP and the catalytic subunit of cyclic AMP-dependent protein kinase. A less-purified preparation of the enzyme is mainly composed of two proteins, with molecular masses about 50 kDa and 25 kDa, the 50 kDa form being phosphorylated at the same site as the homogeneous enzyme. After purification of both proteins by electro-elution, the 25 kDa protein forms a dimer and migrates on SDS/polyacrylamide-gel electrophoresis with molecular mass about 50 kDa. Peptide maps of purified 25 kDa and 50 kDa proteins are identical, indicating that both proteins are formed by the same polypeptide chain(s). It is concluded that rat liver phospholipid methyltransferase can exist in two forms, as a monomer of 25 kDa and as a dimer of 50 kDa. The dimer can be phosphorylated by cyclic AMP-dependent protein kinase.

| S-EPMC1147047 | biostudies-other

Factors affecting the activity of oestradiol hydroxylase in rat liver microsomal subfractions.

Project description:1. Oestradiol hydroxylase activity, as measured by the formation of water-soluble products, was significantly higher in the smooth endoplasmic reticulum of rat liver than in the rough membrane. 2. The isolated membrane fractions retained their activity for at least 6 months if stored at -30 degrees C and were more stable in tris-HCl than in sodium phosphate buffer. 3. The stability of the oestradiol-hydroxylating system was inversely related to lipid peroxidation and was decreased by phospholipases and deoxycholate, which damage the reticular membranes. Ribonuclease had no effect on this system. 4. Added polyribosomes did not influence the metabolism of oestradiol in the smooth membranes but some inhibition in the yield of water-soluble metabolites was produced by corticosterone. 5. The effect of spermine on microsomal hydroxylation was investigated. It is proposed that this polyamine acts either by direct activation of the enzyme complex or by inhibition of the lipid peroxidase pathway in a linked system rather than by stabilization of the reticular membranes.

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Rat liver response to Clofibrate, DEHP or VPA

Project description:The project had 2 goals: 1) To evaluate the transcriptional response of 3 prototypical toxicants (Clofibrate, VPA, and DEHP) on rat lever. 2) To evaluate the impact pooling samples has on data analysis. Keywords = Clofibrate Keywords = Diethylhexyl phthalate Keywords = Phthalic acid bis(2-ethylhexyl ester) Keywords = Sodium Valproate Keywords = Valproic Acid Keywords = VPA Keywords = vehicle Keywords: other

2005-06-02 | GSE2303 | GEO

Some properties of the Ca2+-stimulated ATPase of a rat liver microsomal fraction.

Project description:1. The heavy microsomal fraction from rat liver apparently has very little Ca2+-stimulated ATPase activity, although it has an active, ATP-driven Ca2+ accumulation system. 2. The addition of ionophore A23187 to the ATPase assay, to allow continuous Ca2+ recycling during the assay time, reveals the presence of a substantial Ca2+-stimulated ATPase with Vmax. 160 nmol of Pi/10 min per mg of protein and Km for Ca2+ 0.19 microM. 3. The Ca2+-stimulated ATPase, but not the basal Mg2+-stimulated ATPase, is potently inhibited by orthovanadate. Both the Ca2+-stimulated ATPase and the vanadate inhibition are enhanced by the presence of Mg2+. 4. Ca2+-stimulated ATPase activity is not responsive to calmodulin or the calmodulin antagonist trifluoperazine.

| S-EPMC1154238 | biostudies-other

Kinetic properties of the Ca2+-accumulation system of a rat liver microsomal fraction.

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| S-EPMC1158551 | biostudies-other

Progesterone and oestradiol increase cytosolic Ca2+ in single rat hepatocytes.

Project description:Progesterone (300-400 microM) and oestradiol (25-200 microM) induce a prompt rise in the cytosolic free Ca2+ concentration (free Ca) in single rat hepatocytes, but testosterone, cortisol and dexamethasone do not. These increases are dependent on the presence of extracellular Ca2+. Both progesterone and oestradiol block phenylephrine-induced free Ca oscillations. These data suggest a certain specificity of the response of free Ca to steroids and may explain some of the non-genomic effects of these steroids on hepatocytes.

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Growth hormone and drug metabolism. Acute effects on microsomal mixed-function oxidase activities in rat liver.

Project description:Adult male rats were subjected either to sham operation or to hypophysectomy and adrenalectomy and maintained for a total of 10 days before treatment with growth hormone. Results of the early effects of growth hormone on the activities of the mixed-function oxidases in rat liver over a 96h period after growth-hormone treatment are presented. 2. Hypophysectomy and adrenalectomy result in decreased body and liver weight and decreased drug metabolism (mixed-function oxidases). Concentrations of electron-transport-system components are also decreased. 3. In the hypophysectomized/adrenalectomized rats, growth hormone decreases the activities of the liver mixed-function oxidases and the cytochrome P-450 and cytochrome c reductases, as well as decreasing the concentration of cytochrome P-450 compared with that of control rats. Similar but less dramatic results are obtained with sham-operated rats. 4. It is concluded that whereas growth hormone enhances liver growth, including induction of many enzyme activities, it results in a decrease in mixed-function oxidase activity. Apparently, mixed-function oxidase activity decreases in liver when growth (mitogenesis) increases.

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Retrospective assessment of rat liver microsomal stability at NCATS: data and QSAR models.

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The cell-free synthesis of cytochrome c by a microsomal fraction from rat liver.

Project description:Conditions were investigated for demonstrating the synthesis in vitro of the complete molecule of cytochrome c by isolated liver microsomal systems from partially hepatectomized rats. It was first found that in vivo the early labelled cytochrome c associated with the microsomal fraction required, by comparison with the mitochondrial pool, more drastic conditions of extraction and its binding was less affected by freezing and thawing of the subcellular particles. The procedure of extraction and purification of cytochrome c had to be modified accordingly, to assure the recovery of the recently synthesized molecule. Several subcellular fractions were isolated from regenerating liver with a homogenization medium containing either 5 or 10mm-Mg(2+) and most of them were active in the synthesis of the cytochrome c apoprotein. The microsomal fraction, in the presence of either cell sap or pH5.0 fraction, was also able to incorporate [(59)Fe]haemin, delta-amino[(3)H]laevulic acid and (55)Fe into the prosthetic group of cytochrome c. These experiments confirm firmly the conclusions of our previous results obtained in vivo showing that both the apoprotein and the haem moieties are made and linked together on cytoplasmic ribosomes and only then is the complete molecule transferred to the mitochondria.

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