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 influence of Monensin, Tiamulin and the simultaneous administration of the two substances on the microsomal, mixed function oxidases was studied on cockerels. Monensin was seen to cause a slight depression in the amount of cytochrome P-450 and cytochrome b5 as well as in the activities of aniline-p-hydroxylase, p-nitrophenol-hydroxylase and p-nitroanisole-O-demethylase. Tiamulin induced a moderate increase in the amount of cytochrome P-450 and in the activities of aniline-p-hydroxylase, p-nitrophenol-hydroxylase and aminopyrine-N-demethylase. The combined administration of monensin and tiamulin resulted in marked induction of the microsomal enzymes; the amount of cytochrome P-450 reduced by metyrapone or carbon monoxide increased 2.5 or 2-times, respectively, and the activities of the tested microsomal hydroxylases and demethylases showed also an expressed increase. At the same time the formation of lipid peroxides also markedly increased and the GSH concentration was reduced. In conclusion, the results of the investigations indicate that the simultaneous application of monensin and tiamulin cause a marked induction of the drug-metabolizing microsomal enzymes and a significant increase in the lipid peroxide formation.
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PMID:[The effect of monensin, tiamulin and the simultaneous administration of both substances on the microsomal mixed function oxidases and on the peroxide formation in broilers]. 224 30

The effects of cold-restraint as a physiological stressor on the glutathione (GSH) content of the liver and other tissues were examined in male mice. Mice of the ICR, NIH, ND/4, and B6C3F1 strains subjected to cold-restraint for 2 or 3 h experienced a loss of hepatic GSH concentrations ranging from approximately 15 to 50%. Though 3 of these strains (ICR, NIH, and B6C3F1) experienced hypothermia as result of the cold-restraint treatment, with average decreases in core body temperature ranging from 3.3 to 9.8 degrees C, hepatic GSH levels were depressed in the ND/4 mouse in the absence of changes in core body temperature. The ability of cold-restraint as a stressor to diminish hepatic GSH therefore could not be attributed simply to hypothermia. The decrease in hepatic GSH from cold-restraint in ND/4 mice was paralleled by a decrease in non-protein sulfhydryl (NPSH) content of the liver. In addition to its effects on liver GSH and NPSH concentrations, 1.5 h of cold-restraint stress significantly depressed plasma, heart, kidney, and lung NPSH concentrations. The extent of NPSH depression was equivalent to the GSH depression in the liver, heart, and kidney, despite the observation that the normal contribution of GSH to total NPSH content in these tissues ranged from a high of 89% (liver) to a low of 49% (heart). These results with cold-restraint in the ND/4 mouse suggest that other stressors may significantly depress cellular concentrations of GSH and other thiols, and may thereby render the affected tissues more susceptible to the toxicity of free radicals, electrophilic xenobiotic metabolites, or reactive oxygen species.
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PMID:Depression of glutathione by cold-restraint in mice. 231 51

The ability of morphine and other opioid analgesic drugs to diminish hepatocellular glutathione (GSH) concentrations was examined in ICR mice. When administered intraperitoneally, morphine, hydromorphone, ethylmorphine, l-alpha-acetylmethadol (LAAM), and meperidine all caused a significant decrease in hepatic GSH concentrations in male mice while codeine, methadone, butorphanol, nalbuphine, and pentazocine were without effect even at doses up to those approaching acute lethality. Depression of hepatic GSH equivalent to that observed after ip administration could be elicited by icv administration of small doses of morphine, ethylmorphine, and hydromorphone. LAAM and meperidine were ineffective following icv administration in these experiments. The discrepancy between results following ip versus icv administration of LAAM and meperidine suggests that hepatic metabolism of some opioids may be important for their activity in the CNS, as both norLAAM and normeperidine diminished hepatic GSH when administered by the icv route. The opioid-induced lowering of hepatic GSH does not appear to be sex-dependent since morphine and LAAM produced qualitatively and quantitatively similar effects on hepatic GSH in female mice. Morphine administered icv produced a substantial increase in the hepatotoxicity of two compounds dependent upon GSH for detoxification, acetaminophen and cocaine, as measured by serum alanine aminotransferase activities. These observations indicate that a number of opioid analgesic drugs have the potential to diminish hepatic GSH. Further, these results support earlier studies which indicate that central opioid effects on hepatic GSH are mediated through mu-opioid receptor stimulation. Last, these studies suggest that a centrally initiated opioid action on hepatic GSH may significantly influence the susceptibility of the liver to the effects of some hepatotoxic agents.
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PMID:Depression of hepatic glutathione by opioid analgesic drugs in mice. 247 Dec 91

Cultured type II pneumocyte responses to in vitro normoxia (95% air:5% CO2) or hyperoxia (95% O2:5% CO2) were quantified. Normoxic culture (0 to 96 h) of rabbit type II cells resulted in enhanced cell-monolayer protein and DNA content. During this same time, cellular activities of superoxide dismutase (SOD), catalase, and glutathione peroxidase (GSH Px) decreased. Compared to cultures maintained in normoxia, hyperoxic exposure of cultures resulted in decreased cell-associated protein and DNA content. Exposure to hyperoxia also resulted in cytotoxicity as demonstrated by elevated cellular release of DNA, lactate dehydrogenase (LDH), and preincorporated 8-[14 C]adenine. Cellular catalase and GSH Px activities in hyperoxic cells decreased similarly to normoxic controls. In contrast, cellular SOD activity in hyperoxic cells decreased less than in normoxic cultures. Cellular SOD activity in hyperoxic cultures, when normalized for cellular protein, but not DNA, was greater than normoxic values after 24 to 96 h of exposure. Unlike the decrease in cellular antioxidant enzymes during normoxic and hyperoxic culture, cellular LDH activity increased during both these exposures. Cellular LDH activity in 24 to 96 h hyperoxia-exposed cells increased to a lesser extent than normoxic controls. The extent of depression in LDH activity was dependent on whether the activity was normalized for cellular protein or DNA. Type II pneumocytes, which normally undergo hyperplasia and hypertrophy during hyperoxia in vivo, exhibited oxygen sensitivity in vitro. Exposure of type II cells to hyperoxia in vitro resulted in alterations in cellular SOD and LDH activities, but recognition of such changes were dependent on whether enzymatic activities were normalized for cellular DNA or protein.
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PMID:Responses of type II pneumocyte antioxidant enzymes to normoxic and hyperoxic culture. 250 12

Starvation for 24 h causes a striking fall in glutathione content from 3.19 +/- 0.27 to 1.88 +/- 0.14 (X +/- SEM) mumol/g tissue and of GGT activity from 31.75 +/- 4.17 to 19.49 +/- 3.13 (X +/- SEM) nmol/min/mg protein in the homogenate from whole mucosa of the upper small intestinal segments. This was associated with a significant increase in GSH-Px activity and the content of lipid peroxides (measured by the thiobarbituric assay). On semi-synthetic iron-supplemented diet the activities of GSH-T and GGT were significantly decreased as compared with crude diet. On semisynthetic iron-depleted diet GSH-T and GGT activities were further depressed, but this was accompanied with an additional depression of GSH, glutathione reductase (GSSG-R), and glutathione peroxidase (GSH-Px) activities and lipid peroxide concentrations. Food deprivation significantly lowers the mucosal GSH-content and could lead to a destabilization of this system presumably by increased oxidative stress. As compared to normal "crude" diet, semisynthetic diets and oral iron depletion have been shown to cause a depression of the intestinal GSH system. As a consequence of these effects, the resistance of the small intestinal mucosa toward exogeneous dietary toxins might be reduced.
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PMID:Glutathione and its related enzymes in the small intestinal mucosa of rats: effects of starvation and diet. 256 68

Hepatotoxicity of allyl formate (AF) was studied in trout, to characterize the response of the teleost liver to a mammalian periportal hepatotoxicant. A dose-dependent decrease in liver nonprotein sulfhydryl (NPSH) concentration was observed at 3, 6, and 24 hr following 9.5, 28, and 95 mg/kg) AF with maximal depression seen at 6 hr (51, 40, and 29% control, respectively). Further evidence for glutathione (GSH) protection against AF toxicity was seen when diethylmaleate, a GSH depleting agent (0.6 ml/kg ip), administered 30 min prior to AF (9.5 and 28 mg/kg), increased AF hepatotoxicity (10-fold shift in the dose-response effect on SGPT). Also, N-acetyl-L-cysteine (150 mg/kg ip), a GSH precursor, protected liver against AF toxicity when injected 5 min prior to and 1, 5, and 9 hr after AF (28 and 95 mg/kg). Pyrazole (375 mg/kg ip), an alcohol dehydrogenase inhibitor, given 4 hr before AF (95 mg/kg), attenuated the histopathological effect of AF. These results indicate that AF, once bioactivated by alcohol dehydrogenase, causes significant toxicity in trout liver. GSH protects against AF-induced effects since greater than 50% decreases in liver GSH are required before toxicity is expressed.
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PMID:Mechanism of allyl formate-induced hepatotoxicity in rainbow trout. 271 94

A series of studies were conducted in order to further characterize the previously reported effect of morphine to diminish hepatocellular concentrations of glutathione (GSH) in mice. Naive ICR mice administered morphine (i.p.) in doses up to 1000 mg/kg had diminished hepatic GSH concentrations, with a maximum depletion of approximately 50% occurring at doses of 250 mg/kg or greater. No such effect from an acute challenge with morphine was observed in morphine-tolerant mice. The intracerebro-ventricular administration of the opioid receptor antagonist naltrexone (250 micrograms) completely blocked the hepatic GSH depression resulting from the systemic (i.p.) administration of morphine (100 mg/kg). When morphine (100 micrograms) was administered by the i.c.v. route, GSH concentrations in liver and plasma were significantly altered while heart and kidney were unchanged. Variable responses to i.c.v. morphine were obtained in spleen, stomach and lung. The depression of hepatic GSH was found not to be a consequence of morphine-induced hypoxia or hypothermia, and could not be attributed to intracellular oxidation of GSH.
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PMID:Perturbation of glutathione by a central action of morphine. 275 29

Intravenous doses of buthionine sulfoximine (BSO, NSC 326231), an inhibitor of glutathione synthesis, were eliminated rapidly from mouse plasma in a biexponential manner. The initial phase of the plasma concentration versus time curve had a half-life of 4.9 min and accounted for 94% of the total area under the curve. The half-life of the terminal phase of the curve was 36.7 min and the area accounted for only 6% of the total area under the curve. Plasma clearance of BSO was 28.1 ml/min/kg and the steady state volume of distribution was 280 ml/kg. The oral bioavailability of BSO, based on plasma BSO levels, was extremely low. However, comparable glutathione depletion was apparent after i.v. and p.o. doses of BSO, suggesting a rapid tissue uptake and/or metabolism of BSO. Therefore, due to the rapid elimination of BSO from mouse plasma, plasma drug levels do not directly correlate with BSO-induced tissue glutathione depletion. Administration of multiple i.v. doses of BSO to male and female mice resulted in a marked 88% depletion of liver glutathione at doses of 400-1600 mg/kg/dose. Toxicity of i.v. administered BSO was limited to a transient depression of peripheral WBC levels in female mice given six doses of 1600 mg/kg. Multiple i.v. doses of BSO of up to 800 mg/kg/dose (every 4 h for a total of six doses) did not alter the toxicity of i.v. administered melphalan. However, multiple doses of 1600 mg/kg/dose of BSO did potentiate histopathological evidence of melphalan-induced bone marrow toxicity in 30% of the mice and, additionally, the combination of BSO and melphalan produced renal tubular necrosis in 80% of the male mice. The potentiation of melphalan induced toxicity did not appear to be related to GSH depletion, since: quantitatively similar amount of GSH depletion occurred at lower dose of BSO without any increase in melphalan toxicity.
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PMID:Pharmacokinetics of buthionine sulfoximine (NSC 326231) and its effect on melphalan-induced toxicity in mice. 276 4

Cysteine is required for the synthesis of cosubstrates for two pathways of acetaminophen metabolism: 3'-phosphoadenosine-5'-phosphosulfate (PAPS) for sulfation and glutathione (GSH) for detoxification of the reactive metabolite (N-acetyl-p-benzoquinoneimine, NAPQI). Dietary deficiency of cysteine may reduce hepatic production of PAPS and GSH and thereby reduce metabolism of the drug (by sulfation and detoxification of NAPQI) and hence lead to potentiation of acetaminophen liver injury. Conversely, limitation of sulfur-containing amino acids could result in depression of protein synthesis and hepatic cytochrome P450 levels, and hence in decreased reactive metabolite formation and decreased liver injury. To determine whether the potentiating effects exceed the protective effects, rats were fed isocaloric AIN-76 liquid diets containing various levels of methionine as the sole source of sulfur in the diet for 3 weeks prior to administration of acetaminophen. Sulfur deficiency was assessed by measuring urinary inorganic sulfate levels. Sulfur-deficient diets retarded growth but did not affect nitrogen balance. Sulfur-deficient animals had lower basal levels of hepatic GSH. Pharmacokinetic studies revealed that at low doses of acetaminophen (20 mg/kg), animals fed sulfur-deficient diets metabolized the drug more slowly due to a markedly reduced sulfation capacity, whereas at the high dose of acetaminophen (400 mg/kg), rats that were fed sulfur-deficient diets had a higher clearance of the drug than rats that were fed the complete diet. The increase in clearance was due largely to an enhanced glucuronidation capacity and an enhanced P450-dependent oxidation as indicated by mercapturate formation. Histologic studies revealed that rats fed sulfur-deficient diets showed increases in both incidence and severity of acetaminophen hepatic necrosis. Thus, the potentiating effects exceeded the protective effects. These observations raise the possibility that nutritional inadequacy of sulfur-containing amino acids which could occur during protein malnutrition may similarly enhance susceptibility to acetaminophen liver injury in humans.
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PMID:Effects of sulfur-amino acid-deficient diets on acetaminophen metabolism and hepatotoxicity in rats. 281 88

A number of histamine receptor agonists and antagonists were utilized to study the effects of histamine on hepatocellular reduced glutathione (GSH) concentrations and the potential role of histamine as a mediator of morphine-induced hepatic GSH depression. Administration of histamine, the H1-histamine receptor agonist thiazolylethylamine, the H2-histamine receptor agonist impromidine, or the histamine-releasing substance compound 48/80 resulted in no significant change in hepatic GSH concentrations. The H1-histamine receptor antagonist chlorpheniramine and the H2-histamine receptor antagonist ranitidine were also without significant effect on hepatic GSH and did not antagonize morphine-induced GSH depression. These observations indicate that histamine release following morphine administration does not play a significant role in the subsequent depletion of hepatic GSH.
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PMID:Histamine and hepatic glutathione in the mouse. 288 42


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