Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The temporal variation of HMG-CoA reductase activity in the liver and intestine of swine was investigated. The thin-layer chromatographic method widely used in the assay of the reductase was successfully applied to the porcine enzymes. Parallel circadian rhythms were demonstrated in both hepatic and ileal reductases from mash-fed animals. Peak activity occurred approximately 6 hr after feeding, 2.7-fold over the basal level in the liver, and 1.6-fold in the ileum. A milk-cholesterol diet caused a marked depression of both rhythms (90% in liver, 50% in ileum); however, the hourly variation in activity persisted in both organs. Cholestyramine was found to elevate hepatic activity (2.7-fold throughout the rhythm) without affecting that of the intestine. Clofibrate had no effect on either enzyme at any time during the cycle despite a 34% reduction in serum cholesterol concentrations.
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PMID:Circadian variation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in swine liver and ileum. 728 87

Dolichol is an isoprenoid lipid involved in the assembly of many membrane-bound and secreted glycoproteins. Dolichol biosynthesis can be considered as a branch of the cholesterol biosynthetic pathway subsequent to the reaction catalyzed by beta-hydroxy-beta-methylglutaryl coenzyme A reductase (hydroxymethylglutaryl-CoA reductase, EC 1.1.1.34), the major regulatory enzyme of cholesterol biosynthesis. Changes in reductase activity can also affect the rate of dolichol synthesis. Since the majority of plasma glycoproteins are synthesized by the liver, we have measured the rate of dolichol synthesis in mouse-liver slices after various treatments which alter hepatic beta-hydroxy-beta-methyl-glutaryl-CoA reductase activity in vivo. The rate of hepatic dolichol synthesis was decreased by dietary cholesterol and fasting, and increased by feeding cholestyramine. There is also a diurnal variation in the rate of dolichol synthesis. A plot of the rate of dolichol synthesis versus the rate of cholesterol synthesis suggests that, after the formation of isoprene units, the branch of dolichol biosynthesis is saturated at a lower concentration of isoprene intermediates than is required to saturate the branch of cholesterol biosynthesis. After 2 weeks of cholesterol feeding and the consequent depression of hepatic dolichol synthesis, the rate of [3H]mannose incorporation into liver and plasma glycoproteins was unchanged, indicating that the rate of dolichol biosynthesis was not rate-limiting for total glycoprotein synthesis under these conditions.
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PMID:Regulation of hepatic dolichol synthesis by beta-hydroxy-beta-methylglutaryl coenzyme A reductase. 741 Mar 82

We previously reported that mevalonate starvation elicited by hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors reduced cholesterol accumulation promoted in murine macrophages by acetylated LDL (AcLDL). In the present study we investigated the cellular mechanism of this effect. Our results indicate that the HMG-CoA reductase inhibitors fluvastatin and simvastatin reduce, in a concentration-dependent manner, more than 50% of the 125I-AcLDL degradation by macrophages. This effect was not due to a decrease of lysosomal enzyme activity, and it was paralleled by the retention of AcLDL-associated cholesteryl ester in the incubation medium. The ability of fluvastatin to inhibit AcLDL degradation was completely overcome by mevalonate and its derivative geranylgeraniol. Evaluation at 4 degrees C of 125I-AcLDL binding to plasma membrane suggested that the inhibitory effect of fluvastatin on lipoprotein catabolism was not due to a decreased expression of scavenger receptors. Fluorescent microscope analysis of cellular internalization of AcLDL labeled with the fluorochrome 3,3'-dioctadecyl indocarbocyanine demonstrated that fluvastatin inhibits lipoprotein endocytosis, an effect reversed by mevalonate. Studies performed with native 125I-LDL indicated that fluvastatin did not inhibit but rather increased the degradation of LDL taken up by the normal LDL receptor. These results exclude a generalized depression of the cellular endocytotic activity by the drug. The ability of fluvastatin to reduce AcLDL catabolism and cholesterol esterification was more pronounced in cholesterol-enriched macrophages compared with normal cells. In conclusion, the present results demonstrate that HMG-CoA reductase inhibitors may reduce the in vitro cholesterol accumulation in macrophages by inhibiting AcLDL endocytosis.
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PMID:HMG-CoA reductase inhibitors reduce acetyl LDL endocytosis in mouse peritoneal macrophages. 767 Sep 49

Serum depletion of exponentially growing normal human fibroblasts resulted in a moderate depression of the activity of HMG-CoA reductase which occurred simultaneously to the onset of growth arrest of the cells. Specific inhibition of HMG-CoA reductase using mevinolin also resulted in growth arrest. PDGF counteracted the suppressive effect of serum depletion on HMG-CoA reductase activity and cell growth. The growth inhibitory effect of serum depletion and mevinolin was correlated to a decreased biosynthesis of dolichols, in particular of dolichol-20. If PDGF was present in the serum-free medium a high rate of dolichol synthesis was maintained. This effect was mediated not only through an increased HMG-CoA reductase activity. PDGF also increased the incorporation of mevalonate into dolichols, once again into dolichol-20 in particular. In contrast to HDF, the growth of virus-transformed human fibroblasts was not decreased following serum depletion. This was correlated to a sustained activity of HMG-CoA reductase and a sustained dolichol-20 synthesis. In order to block growth and dolichol synthesis of the transformed fibroblasts a stronger inhibition of HMG-CoA reductase activity was required than in the normal cells. Conditioned medium isolated from the transformed cells was found to maintain a high growth rate and a high HMG-CoA reductase activity in serum-depleted HDF. In addition, the incorporation of mevalonate into dolichols was increased. The present data raise the possibility that PDGF or related factors, through autocrine loops, may contribute to the maintenance of a high dolichol synthesis in tumor cells.
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PMID:Effect of virus-transformation and growth factor stimulation on isoprene biosynthesis in human fibroblasts: a correlation to cell growth. 776 98

The effects of the addition of a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, simvastatin, to the medium on sterol synthesis and phosphatidylcholine (PC) synthesis were studied in HepG2 cells. The cells were cultured with simvastatin at concentrations of 10(-7) and 10(-6) mol/L for 6 hours, and radioactive lipid precursors were added 1 hour before harvesting. Simvastatin inhibited cholesterol synthesis from [14C]acetate in a dose-dependent manner. It also decreased the incorporation of [14C]choline into PC by 30%; this decrease was accompanied by a decrease in phosphocholine cytidylyltransferase activity in cell homogenates. Simvastatin had no significant effects on the incorporation of [3H]glycerol into phospholipids. These data indicate that simvastatin has two different functions: inhibition of HMG-CoA reductase and depression of de novo synthesis of PC via the cytidine diphosphate-choline pathway, which, in turn, may result in a decrease in plasma lipid levels.
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PMID:Effects of simvastatin, a cholesterol synthesis inhibitor, on phosphatidylcholine synthesis in HepG2 cells. 806 16

Key enzymes of cholesterol metabolism were studied in two inbred strains of rabbits with hyper- or hyporesponse of serum cholesterol to dietary cholesterol. Baseline 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase activity in liver was similar in hypo- and hyperresponders, but that in intestine was twofold higher in the hyporesponders. The addition of cholesterol (3 g/kg) to the diet caused similar depression of hepatic HMG-CoA reductase activity in the two strains, whereas intestinal HMG-CoA reductase activity was significantly reduced in hyporesponders but not in hyperresponders. Cholesterol feeding induced higher free cholesterol concentrations in hepatic and intestinal microsomes of both hypo- and hyperresponders and higher activity of hepatic acyl-CoA:cholesterol acyltransferase (ACAT). Hepatic ACAT activity was significantly lower in cholesterol-fed hyperresponders than in hyporesponders, which may have contributed to the observed higher free cholesterol concentrations in hepatic microsomes of cholesterol-fed hyperresponders. Intestinal ACAT activity was similar in hypo- and hyperresponders; cholesterol feeding tended (P = 0.11) to elevate the activity of this enzyme. Hepatic cholesterol 7 alpha-hydroxylase activity was significantly higher in cholesterol-fed hyperresponders than in hyporesponders; it was slightly depressed after cholesterol loading in both rabbit strains.
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PMID:Dietary cholesterol-induced down-regulation of intestinal 3-hydroxy-3-methylglutaryl coenzyme A reductase activity is diminished in rabbits with hyperresponse of serum cholesterol to dietary cholesterol. 846 71

In this study we show that proliferation of cycling tumor-transformed human fibroblasts (line 90VAV1) is blocked specifically in G1 by HMG CoA reductase inhibition. This inhibition also resulted in a drastic depression of N-linked glycosylation, measured as incorporation of radioactive glucosamine into acid-insoluble material. Following addition of mevalonate to cells arrested by HMG CoA reductase inhibitors, the depression of N-linked glycosylation was overcome and the cells initiated DNA synthesis. However, if the mevalonate-induced increase in protein glycosylation was prevented, due to addition of tunicamycin (an inhibitor of N-linked glycosylation), the cells were not able to proliferate. If instead tunicamycin was added 4 h after the addition of mevalonate, the cells synthesized DNA normally. Upon addition of tunicamycin, to cycling cells the progression through G1 was blocked in a similar way to that following HMG CoA reductase inhibition. Taken together, our data provide strong evidence for involvement of N-linked glycosylation in the mevalonate-controlled cell cycle progression and growth activation of tumor-transformed human fibroblasts.
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PMID:Role of N-linked glycosylation in cell-cycle progression and initiation of DNA synthesis in tumor-transformed human fibroblasts. 847 9

We report on adverse drug reactions to statins recorded internationally and in Norway. The use of HMG-CoA reductase inhibitors (statins) has increased with a factor of 30 in Norway over the period 1989-96. Recently published clinical trials conclude that statins are safe; adverse drug reactions being infrequent and non-serious. The reactions observed are mostly increased hepatic enzymes and myopathy. Data from the Norwegian spontaneous reporting system, and from WHO's international database covering the period of 1988-95, includes reports of adverse drug reactions relating to other organ systems, such as the nervous system, the gastrointestinal tract, skin and cardiovascular organs. Psychiatric disorders represent 15% of the reactions to statins in the Norwegian database. Reactions include aggression, nervousness, depression, anxiety, sleeping disorders and impotence. The pharmacological mechanisms are not elucidated, but may be an effect of falling serum cholesterol.
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PMID:[Statins--the pattern of adverse effects with empahsis on mental reactions. Data from a national and an international database]. 941 59

The present study was undertaken to investigate the effects of D003, a mixture of very long chain saturated fatty acids isolated and purified from sugar cane wax, on cholesterol biosynthesis in cultured fibroblasts. Cholesterol biosynthesis is regulated through feedback regulation of at least two sequentially acting enzymes, 3-hydroxy-3-methyl coenzyme A (HMG-CoA) synthase and reductase. They are up-regulated when sterol levels fall and down-regulated when sterol levels rise. The exposure of cultured fibroblasts to a lipid-depleted medium (LDM) and D003 (0.05-50 microg ml(-1)) for 12 h inhibited, in a dose-dependent manner, cholesterol biosynthesis from 14C-labelled acetate (33-68%). The addition of D003 at concentrations inhibiting cholesterol biosynthesis from labelled acetate significantly decreased incorporation of radioactivity from 3H2O into sterols, but not from 14C-mevalonate. These data indicate that D003 inhibits cholesterol biosynthesis by interfering with early steps of cholesterol biosynthetic pathway. We reasoned that D003 acts directly on HMG-CoA reductase, the main regulatory enzyme of cholesterol biosynthetic pathway. However, when enzyme activity was measured in cell extracts in the presence of various concentrations of D003 (0.5-50 microg ml(-1)), reductase activity was not inhibited. Thus, there was no evidence for a competitive or non-competitive inhibition of enzyme activity by D003. Treatment with D003 significantly suppressed (68%) the enzyme up-regulation when cells were cultured in LDM, which suggests a depression of de novo synthesis of HMG-CoA reductase and/or a stimulation of its degradation. However, since the suppressive action of D003 on cholesterol biosynthesis was observed in metabolic conditions under which synthase up-regulation was also enhanced, we cannot rule out a possible effect of D003 on HMG-CoA synthase. Thus, further studies are needed to clarify the precise mechanism of the inhibitory effect of D003 on cholesterol biosynthesis.
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PMID:Inhibition of cholesterol biosynthesis in cultured fibroblasts by D003, a mixture of very long chain saturated fatty acids. 1159 64

Elevated glucocorticoid levels are associated with many diseases, including age-related depression, hypertension, Alzheimer's disease, and acquired immunodeficiency syndrome. Cortisol-lowering agents could provide useful complementary therapy for these disorders. We examined the effect of procaine and procaine in a pharmaceutical formulation on adrenal cortical steroid formation. Procaine inhibited dibutyryl cyclic AMP (dbcAMP)-induced corticosteroid synthesis by murine Y1 and human H295R adrenal cells in a dose-dependent manner without affecting basal steroid formation. Treatment of rats with the procaine-based formulation reduced circulating corticosterone levels. This steroidogenesis-inhibiting activity of procaine was not observed in Leydig cells, suggesting that the effect was specific to adrenocortical cells. In search of the mechanism underlying this inhibitory effect on cAMP-induced corticosteroidogenesis, procaine was found to affect neither the cAMP-dependent protein kinase activity nor key proteins involved in cholesterol transport into mitochondria, cytochrome P450 side chain cleavage enzyme expression, and enzymatic activities associated with cholesterol metabolism to final steroid products. However, procaine reduced in a dose-dependent manner the 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA) activity and the dbcAMP-induced HMG-CoA reductase mRNA levels by affecting mRNA stability. These data suggest that the inhibitory effect of procaine on cAMP-induced corticosteroid formation is due to the reduced synthesis of cholesterol. This modulatory effect of procaine on HMG-CoA reductase mRNA expression was also seen in dbcAMP-stimulated Hepa1-6 mouse liver hepatoma cells. Taken together, these results suggest that procaine may provide a pharmacological means for the control of hormone-induced HMG-CoA reductase mRNA expression and hypercortisolemia.
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PMID:Inhibition of adrenal cortical steroid formation by procaine is mediated by reduction of the cAMP-induced 3-hydroxy-3-methylglutaryl-coenzyme A reductase messenger ribonucleic acid levels. 1456 37


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