UMLS:C0011570 - FACTA Search

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)

Effects of doxapram, a respiratory stimulant, on the action of other drugs and the activity of the hepatic drug-metabolizing enzyme were studied in mice. The hypothermic effect induced by aminopyrine and the muscle relaxant effect induced by meprobamate were potentiated by the pretreatment with doxapram 60 min before. Furthermore, doxapram significantly enhanced the lethalities of picrotoxin and strychnine and the analgesic actions of aminopyrine and morphine. The plasma concentration of aminopyrine or pentobarbital in doxapram-treated mice was higher than those in untreated mice, and the plasma concentration of normustard related to an active metabolite of cyclophosphamide after the administration of cyclophosphamide was lower in doxapram-treated mice. On the other hand, doxapram (50 mg/kg, i.p.) reduced remarkably the activities of aminopyrine N-demethylase and aniline hydroxylase in the hepatic 9,000xg supernatant fraction, and also reduced the cytochrome P-450 contents in hepatic microsomes. However, no significant alteration by doxapram was observed on the activities of NADH-ferricyanide reductase and NADPH-cytochrome c reductase and cytochrome b5 contents. It seems likely that the mechanisms of the interaction between doxapram and combined drugs involved the depression of the hepatic drug-metabolizing system in microsomes and a subsequent variation of drug level in the plasma.
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PMID:Effect of doxapram on the action of other drugs and the hepatic drug-metabolizing system in mice. 713 53

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

1. The goal of this study was to characterize the fatigability, contractile relaxation properties, electrophysiological responses, and histochemical properties of the human paralyzed soleus muscle to determine its relative plasticity. 2. Acute (< 6 wk, n = 3) and chronic (> 1 yr, n = 10) paralyzed individuals had the tibial nerve activated with a 20-Hz square wave delivered for 330 ms every second for 4 min. The soleus muscle peak torque, one-half relaxation time (1/2RT), normalized maximum rate of relaxation (nMRR), and mass muscle action-potential amplitude (M wave) were computed every 30 s. A soleus muscle biopsy was evaluated for myosin adenosine triphosphatase enzyme (ATPase; pH 9.4, 4.6, and 4.2) and nicotinamide adenine dinucleotide tetrazolium reductase (NADH-TR). 3. In the chronically paralyzed group the torque was significantly reduced within 30 s of the fatigue protocol. The 1/2RT and nMRR were also significantly changed within 30 s, supporting that muscle relaxation was prolonged. No significant changes were present at comparable times during the same 4-min fatigue protocol applied to the acutely paralyzed soleus muscle. M-wave amplitude was significantly reduced in the chronic group, but only at 3 min of the fatigue protocol. Conversely, no significant changes occurred to the M waves of the acute group. 4. The correlation was high between torque and nMRR (r = 0.88-0.97) and torque and 1/2RT (r = 0.88-0.96) for each chronic subject. A close association was also found between 1/2RT and nMRR (r = 0.88-0.92) for each chronic subject. Because these variables changed minimally in the acutely paralyzed group, a lower correlation was present (r = 0.45-0.52). 5. Torque was weakly correlated to M-wave amplitude (r = 0.55) for the chronically paralyzed group. The greatest change in torque occurred at a time (0-65 s) when the least amount of change occurred in the M-wave amplitude, suggesting that the source of fatigue was within the contractile mechanism and not attributable to neuromuscular transmission compromise. 6. Despite a close association between torque and relaxation properties during fatigue of the chronically paralyzed soleus muscle, there was a significant dissociation after 5 min of recovery. Torque recovered to 60%, whereas the relaxation properties were consistently fully recovered. This suggests that the mechanism causing torque reduction covaried with the mechanism leading to prolonged relaxation during fatigue, but during recovery the two mechanisms no longer covaried. M-wave amplitude was also completely recovered at 5 min despite continued torque depression.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Fatigability, relaxation properties, and electromyographic responses of the human paralyzed soleus muscle. 766 32

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

The primary defence mechanism of myocytes against peroxides and peroxide-derived peroxyl and alkoxyl radicals is the glutathione redox cycle. The purpose of the present study was to increase the turnover rate of this cycle by stimulating the glutathione peroxidase catalysed reaction (2GSH-->GSSG), the glutathione reductase catalysed reaction (GSSG-->2GSH), or both. Neonatal rat heart cell cultures were subjected to a standardized protocol of oxidative stress using 80 mumol.l-1 cumene hydroperoxide (CHPO) for 0-90 min. The consequences of this protocol were described in terms of cellular concentrations of GSH, GSSG, NADPH and ATP, formation of malondialdehyde (MDA), release of GSSG and of ATP catabolites, depression of contraction frequency, cellular calcium overload, and enzyme release. Trolox-C, an analogue of vitamin E, accelerated the glutathione peroxidase reaction leading to lowering of GSH concentration and the GSH/GSSG ratio, less MDA formation, diminished negative chronotropy, delayed calcium overload, and less enzyme release. Glucose was used to accelerate the glutathione reductase reaction by supplying NADPH, leading to higher GSH concentration and a higher GSH/GSSG ratio, less MDA formation, diminished negative chronotropy, unchanged development of calcium overload, and less enzyme release. As a full turn of the glutathione redox cycle involves both the peroxidase and the reductase reactions, the combination of Trolox-C and glucose was superior to either of the two alone: 90 min following addition of CHPO together with Trolox-C and glucose, the GSH concentration and the GSH/GSSG ratio were almost normal, MDA formation was extremely low, calcium overload was markedly delayed, and enzyme release hardly occurred at all. Cells remained beating in the observation period of 30 min. We conclude that the capacity of the glutathione redox cycle to withstand oxidative stress can be increased by stimulation of either the peroxidase reaction or the reductase reaction, and that optimal redox cycling is achieved by stimulation of both reactions.
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PMID:Protection of myocytes against free radical-induced damage by accelerated turnover of the glutathione redox cycle. 767 3

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

Anthraquinone dyes are utilized by the military in colored-smoke grenades. During production, workers in munitions plants may be exposed to fugitive emissions of these dyes or mixtures thereof. The effects of a prototype violet dye mixture (VDM) consisting of Disperse Red 11 (DR11), [1,4-diamino-2-methoxy-anthraquinone] and Disperse Blue 3 (DB3) [1-methylamino-4-hydroxyethylamino-anthraquinone] on F344 male and female rats have been investigated. Acute 1-day inhalation exposures (6 hr) to VDM were conducted at 1000, 300, 100, 70, 40, and 10 mg/m3, with an additional exposure to 40 mg/m3 6 hr/day for 5 days; 4.22 +/- 2.1 microns (MMAD +/- delta g). Lung burdens of dye, general histopathology, and/or liver function were evaluated at 0, 3, and 7 days postexposure. Unexpected lethality due to severe liver damage was observed with acute exposures of > or = 300 mg/m3 and in the 5-day 40 mg/m3 exposures. Centrilobular degeneration and necrosis of liver cells was concentration-dependent with inhalation of VDM > or = 40 mg/m3. In addition, nasal olfactory epithelium exhibited degeneration and necrosis with acute exposures > or = 10 mg/m3. Lung instillations at 250, 500, and 1000 micrograms of the VDM revealed no lung or liver toxicity. Because per os exposure due to preening was suspected as a major exposure route, a gavage study with the VDM and its two component dyes DR11 and DB3 (800 mg/kg) was undertaken. One day following gavage with DR11 or DB3, serum enzymes indicative of liver toxicity (LDH, SGPT, SDH, and ICDH) were slightly elevated (1-6x control). However, rats gavaged with VDM had serum enzyme levels 10-100x control by Day 1 after gavage, indicating acute liver toxicity. Activities of liver enzymes involved in xenobiotic and glutathione metabolism were also acutely affected. All of the dyes caused various degrees of induction of glucose-6-phosphate dehydrogenase, glutathione reductase, glutathione peroxidase, and nonprotein sulfhydryls. The enzymes involved in xenobiotic metabolism (glutathione S-transferase, NADPH cytochrome-c reductase, and P450) were also elevated by the two component dyes, in contrast to their significant depression with VDM treatment. The similarity between the liver and olfactory epithelium effects of these compounds and the lack of pulmonary tissue effects is not fully understood, but the interaction of the individual dyes as VDM emphasizes the need to assess chemicals such as the anthraquinones as their likely-to-be-encountered mixtures.
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PMID:Toxicity of an anthraquinone violet dye mixture following inhalation exposure, intratracheal instillation, or gavage. 812 3

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

We investigated the expression of the cytochrome P450 isozyme, CYP1A1, during the course of tumor development and examined the distribution of the CYP1A1 protein in hyperplastic foci, adenomas and carcinomas. The expression of NADPH-cytochrome P450 reductase, a flavoprotein that mediates the reduction of cytochrome P450, was also determined. Mice were administered urethane (1 mg/g body wt) and were killed at 10, 22 and 52 weeks to coincide with the time at which hyperplastic foci, adenomas and carcinomas were established, respectively. Protein immunoblotting revealed that the antibody for CYP1A1 detected a protein band of approximately M(r) 56,000 in microsomes from mice treated with beta-naphthoflavone. The antibody for NADPH-cytochrome P450 reductase detected a protein band of approximately M(r) 79,000 in microsomes from control mice and mice treated with beta-naphthoflavone. Immunohistochemical studies showed that CYP1A1 was not detected constitutively in the lungs of both non-tumor- and tumor-bearing mice. Treatment with beta-naphthoflavone evoked high induction of CYP1A1 in morphologically normal tissues of all mice, with localization of the protein mainly in endothelial and alveolar type II cells. In contrast, inducibility of CYP1A1 by beta-naphthoflavone was markedly reduced in early hyperplastic foci seen 10 weeks after urethane exposure. At 22 weeks, CYP1A1 was found at low levels in both solid and papillary tumors, whereas at 52 weeks, lung carcinomas were devoid of expression of this protein. However, CYP1A1 inducibility was highly expressed in late hyperplastic foci manifested at 52 weeks. NADPH-cytochrome P450 reductase was expressed in morphologically normal lung tissue of all mice under control conditions and after treatment with beta-naphthoflavone, and was localized mainly in Clara and alveolar type II cells. In contrast, reductase expression in all tumor sites was diminished and closely paralleled that of CYP1A1. These results demonstrated progressive depression of induced CYP1A1 and reductase expression in early hyperplasias, adenomas and carcinomas, suggesting that the co-ordinate regulation of both enzymes is highly conserved during tumor development. Furthermore, these findings suggested diminished capabilities for metabolic activation of potential toxicants and/or carcinogens after neoplastic transformation.
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PMID:Alterations in expression of CYP1A1 and NADPH-cytochrome P450 reductase during lung tumor development in SWR/J mice. 856 21

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