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)

Phenytoin is one of the most commonly used anticonvulsants in pregnant epileptic women. Unrelatedly, the drug is also an inducer of hepatic drug metabolizing enzymes. Considering these facts, we wanted to determine if maternal treatment with therapeutic-like doses for the rat of phenytoin would produce long-term defects in the metabolism and action of drugs in the dams' adult offspring. We found that peripartum exposure to phenytoin resulted in a significant depression in the maximal velocities of hepatic microsomal aminopyrine N-demethylase in the 28-day-old male and female offspring. When the animals were 4-to-5-month old adults, the maximal velocities for the demethylase and hexobarbital hydroxylase remained subnormal in the males but were elevated in the females exposed to the highest therapeutic-like dose of phenytoin. Hexobarbital-induced sleeping time measurements were in agreement with enzyme kinetic analyses. Lastly, the hepatic monooxygenases of the adult male and female rats exposed, perinatally, to all but the lowest dose of phenytoin, were much less responsive to the inductive effects of several low doses of phenobarbital. The results suggest that levels of phenytoin that may be therapeutic for the mother can produce defects in the developing hepatic monooxygenase system of the perinates, which can then permanently affect drug metabolism and action in adulthood. Furthermore, by disrupting the development of hepatic enzyme induction mechanisms, perinatal exposure to phenytoin may irreversibly alter an important homeostatic mechanism that is normally responsive to daily exposure to low levels of various endogenous and exogenous inducing agents.
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PMID:Persistent defects in the hepatic monooxygenase system of adult rats exposed, perinatally, to maternally administered phenytoin. 372 6

The mechanisms of toxicity and sensitization by the radiosensitizer misonidazole [1-(2-nitro-1-imidazolyl)-3-methoxy-2-propanol] are not well understood. We report here on the inhibition of total glutathione peroxidase (GSHPx), selenium-dependent glutathione peroxidase (selenium-GSHPx) and glutathione transferase (GSHTx) activities by misonidazole. Mouse liver cytosol GSHPx and selenium-GSHPx were inhibited in vitro with 0.5 mM misonidazole. On administration of the drug intraperitoneally (800 mg/kg) to mice, it was found that GSHPx, selenium-GSHPx, and GSHTx were inhibited in homogenate, cytosol, and microsomal fractions of mouse liver. GSHPx was depressed in all fractions up to 60-70% of control values, with maximum depression occurring in the cytosol and homogenate fractions in less than 2 hr. Recovery of activity was slower in the microsomes. In general, the pattern of depression of selenium-GSHPx was parallel to that of GSHPx except in microsomes, where GSHPx is minimal. Quantitatively, selenium-GSHPx was least affected. GSHTx was inhibited 70-80% of control values in cytosol and homogenate with recovery by 24 hr, whereas a second period of depression occurred at 24 hr in the microsomes. The inhibition of peroxide-metabolizing enzymes may lead to elevation of intracellular peroxide levels, contributing to the radiosensitizing effect and/or toxicity of misonidazole.
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PMID:Inhibition of glutathione peroxidase and glutathione transferase in mouse liver by misonidazole. 375 20

Utilizing a specific "low substrate concentration technique", intrasynaptosomal MAO-A and MAO-B activities within the rat brain noradrenaline system were studied. It was found that mainly MAO-A was localized intrasynaptosomally, whereas MAO-B contributed with less than 15% of the total intrasynaptosomal MAO activity, a phenomenon that was also observed within the central dopamine system. It is suggested that the intrasynaptosomal pool of MAO in the noradrenaline and the dopamine systems may reflect the density of innervation of the respective system throughout the brain. In addition, the effects of various selective monoamine oxidase (MAO) inhibitors on the noradrenergic intrasynaptosomal MAO activity as well as on the neuronal firing rate of noradrenaline containing cells in the locus coeruleus (LC) were investigated. Pretreatment with the MAO-A selective inhibitors clorgyline (10 mg/kg, i.p., 1 h) or (+)-FLA 336 (1 mg/kg, i.p., 1 h) caused a significant depression (40%) of mean spontaneous firing rate of LC neurones, randomly encountered throughout the LC. The MAO-B selective inhibitor pargyline (10 mg/kg, i.p., 1 h) was found to lack effect in this regard. However, pretreatment with (-)-deprenyl (10 mg/kg, i.p., 1 h), equally a selective MAO-B inhibitor, markedly suppressed the spontaneous firing rate of LC units. This inhibition by (-)-deprenyl was blocked by pretreatment with SK&F 525 A (50 mg/kg, i.p., 30 min), an inhibitor of microsomal drug metabolizing enzymes. Thus, the depression of LC units by (-)-deprenyl seems to be executed by a metabolite, e.g. l-amphetamine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Relation between brain monoamine oxidase (MAO) activity and the firing rate of locus coeruleus neurons. 376 38

The synergistic hepatotoxicity of dietary disulfiram (DSF) with 1,2-dichloroethane (DCE) subchronically administered by inhalation at three concentration levels (150, 300, and 450 ppm) was studied. The criteria for hepatotoxicity were treatment-related increases in serum activities of sorbitol dehydrogenase, 5'-nucleotidase, and alkaline phosphatase, and in liver-to-body weight ratios. DSF alone did not elicit these responses while DCE at the highest concentration level increased liver-to-body weight ratios and the activity of 5'-nucleotidase. Exposure to DSF alone decreased cytochrome P450 levels, but in combination with DCE, the decrement of cytochrome P450 was additive in a DCE concentration-dependent manner. However, depression of cytochrome P450 by DCE alone was not concentration dependent. Although DSF and DSF/DCE combination increased the activity of glutathione S-transferases (GSTs), both DSF and DCE singly and in combination increased the tissue levels of reduced glutathione (GSH). Evidence is presented showing that the potentiation of the hepatotoxicity of DCE observed in the presence of DSF may be due to an inhibition of microsomal mixed-function oxidase-mediated metabolism of DCE and to a compensatory increase in DCE metabolism to reactive metabolites generated by GST-mediated conjugation of DCE with GSH.
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PMID:Interaction between 1,2-dichloroethane and tetraethylthiuram disulfide (disulfiram). II. Hepatotoxic manifestations with possible mechanism of action. 378 26

A total of 22 patients with advanced measurable colorectal carcinoma were treated with human lymphoblastoid interferon, 15 X 10(6) U/m2 im 3 times a week, in a trial designed to evaluate therapeutic activity, toxic effects, and biological response modification. One partial response (4.5% response rate) was observed which lasted 4 months. Sixty-eight percent of the patients required dose reduction for excessive toxicity, primarily constitutional symptoms. One patient developed phenobarbital toxicity, a previously undescribed side effect thought to be related to interferon-induced depression of hepatic microsomal enzymes required for drug metabolism. Treatment was associated with an increase in peripheral blood natural killer (NK) cell activity and the activity of an interferon-induced enzyme, 2'-5' oligoadenylate synthetase. The increase in NK cell activity was observed only in patients whose pretreatment NK cell activity was below normal. No induction of serum factors inducing differentiation of myeloid leukemic cell lines was documented. We conclude that human lymphoblastoid interferon, at the dose and schedule tested, has minimal antitumor activity as a single agent in advanced colorectal cancer and induces unacceptable toxicity in the majority of such patients. Recent literature suggesting a possible role for interferon alpha in combination with other drugs in the treatment of colorectal cancer is discussed.
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PMID:High-dose human lymphoblastoid interferon in metastatic colorectal cancer: clinical results and modification of biological responses. 379 Dec 67

The pretreatment of calves with a single dose of 10 mg kg-1 dieldrin or 21 daily doses of 10 mg kg-1 phenobarbitone increased the toxicity of diazinon as reflected by the development of more severe clinical signs and greater depression in whole blood cholinesterase activity in the pretreated calves. Induction by dieldrin or phenobarbitone of the hepatic microsomal enzyme amidopyrine-N-demethylase was also accompanied by a concurrent rise in the liver carboxylesterase activity.
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PMID:Effect of pretreatment with hepatic microsomal enzyme inducers on the toxicity of diazinon in calves. 380 24

A functional state of microsomal enzymatic system was studied in liver tissue of rats within 24, 48 and 72 hrs after surgical operation. Factors of operational treatment and of postoperational period were shown to inhibit distinctly amidopyrine demethylase as well as to decrease the content of cytochromes P-450 and b5 and the glycogen concentration in liver tissue. Content of lactic and pyruvic acids was increased in blood. Depression of the functional state of liver microsomes, occurred as a result of hypoxia, appears to be responsible for the phenomenon of elevated drug toxicity during postoperational period.
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PMID:[The state of the microsomal oxidative system of the rat liver in the postoperative period]. 381 Dec 81

A novel aspect of the regulation of heme biosynthesis and cytochrome P-450 concentration in rat adrenals, as pertains to the repressive role of testosterone, is described. Also, the presence of a sex difference in the activities of delta-aminolevulinate (ALA) synthetase and heme oxygenase, as well as the concentrations of heme and cytochrome P-450 in the adrenal mitochondrial and the microsomal fractions, are defined. The female rats displayed a nearly 2-fold higher value for the listed parameters. Castration of rats caused an elevation of ALA synthetase activity to approximate that of the female rats, whereas testosterone replacement depressed the enzyme activity to the level of the sham-operated animals. Moreover, female rats treated with testosterone showed a marked depression in adrenal ALA synthetase activity. This was accompanied by significant reductions in the mitochondrial and microsomal contents of cytochrome P-450 and heme. Heme oxygenase activity was neither altered by castration nor by the testosterone treatment of castrated and female rats. It is suggested that the adrenal ALA synthetase activity is regulated by plasma testosterone levels which, in turn, regulates the production of heme and the cellular levels of heme and cytochrome P-450. The mode of action of testosterone appears to be repressive in nature.
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PMID:Sex difference in adrenal heme and cytochrome P-450 metabolism: evidence for the repressive regulatory role of testosterone. 384 Feb 3

Adrenochrome uptake and its subcellular distribution were examined using isolated perfused rat heart preparation. The heart was perfused for 30 min with a medium containing 1 to 50 mg/l of 14C-adrenochrome and the subcellular fractions were isolated to measure their radioactivities. A decline in contractile force, a rise in resting tension and an increase in adrenochrome uptake by the heart were seen to depend upon the time of perfusion and the concentration of adrenochrome in the medium. The sarcolemmal fraction had the highest uptake of adrenochrome and this was followed by the microsomal fraction; some accumulation of adrenochrome was also observed in the myofibrillar and mitochondrial fractions. Either 10 or 20 min reperfusion of the heart previously exposed to 25 mg/l of adrenochrome, resulted in approximately 50 or 37% of the radioactivity remaining in the heart; this indicates irreversible binding of adrenochrome to the tissue. Reperfusion of the heart showed restoration of the resting tension but the contractile force did not show any recovery. Propranolol and iproniazid, which have been shown to inhibit the adrenochrome induced cardiotoxicity, reduced adrenochrome uptake by the heart, and prevented adrenochrome-induced depression in contractile force and rise in resting tension. These results indicate that adrenochrome is taken up by the heart and induces cardiac disturbances through its action on different subcellular organelles in the myocardium.
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PMID:Adrenochrome uptake and subcellular distribution in the isolated perfused rat heart. 385 Jul 68

A novel effect of metal ions in the brain is described. Mn was found to alter heme metabolism and the cytochrome P-450-dependent mixed-function oxidase activities in rat brain. A more than 2-fold increase in benzo(alpha)pyrene hydroxylase and 7-ethoxycoumarin deethylase activities were observed in the brain of rats treated for 7 days with Mn. The increases were regionally distributed; the highest elevations were observed in the hippocampus, pons and the caudate putamen. Moreover, in rats treated with Mn for 1 or 7 days a marked depression in the activity of the mitochondrial ALA synthetase was observed. The activity of the microsomal heme oxygenase was also inhibited at 7 days, but not 1 day, after Mn treatment. These inhibitions were reflected in an initial decrease, followed by a rebound return to normal, in the concentration of cytochrome P-450 in the brain. Mn was ineffective in vitro in altering heme and drug metabolism activities. It is suggested that Mn-mediated alterations in heme metabolic activities promote changes in the composition of cytochrome P-450 species in the brain microsomal fractions, such that the relative concentrations of the molecular species which catalyse aryl hydrocarbon hydroxylase activity become selectively increased.
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PMID:Regulation of heme and drug metabolism activities in the brain by manganese. 392 Oct 22


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