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)

After coronary occlusion and reflow, carbohydrate catabolism is enhanced, whereas fatty acid utilization is delayed. To test the hypothesis that "stunning" of fatty acid use by ischemic heart reflects reduced fatty acid transport into the mitochondria, two activities involved in the transport were examined: carnitine-acylcarnitine translocase and carnitine palmitoyltransferase II (CPT II). The maximal velocity for carnitine exchange of the translocase is reduced 55% in mitochondria isolated from ischemic canine heart (60-min left circumflex occlusion). Mitochondria from ischemic heart show 50% depletion in total matrix glutathione, a 200% increase in glutathione disulfide (GSSG), and an 80% decrease in the ratio of reduced glutathione (GSH) to GSSG, suggesting that the loss of translocase activity may be a consequence of protein sulfhydryl modifications. In support of this, treatment of these mitochondria with the sulfhydryl-reducing agents, GSH or dithiothreitol, restores carnitine exchange to control. Partial return of mitochondrial GSH and a decrease in GSSG are observed with a 20-min reperfusion of the ischemic myocardium. Continued depression in carnitine exchange with reperfusion suggests that other mechanisms may prevent restoration of activity. Import of palmitoylcarnitine on the translocase is coupled to palmitoyl-CoA production by CPT II. Mitochondria from ischemic heart with decreased coupling activity also have the lowest palmitoylcarnitine-supported respiratory rates, suggesting that in severely ischemic tissue the translocation-transesterification sequence may become rate limiting to fatty acid oxidation.
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PMID:Carnitine-acylcarnitine translocase in ischemia: evidence for sulfhydryl modification. 312 91

There is controversy as to whether or not the acute cochlear toxicity of ethacrynic acid (EA) is dependent upon its metabolic conversion to EA-cysteine via conjugation with glutathione. In order to investigate this we examined the acute effects of EA on cochlear potentials in guinea pigs in which glutathione levels were decreased by prior administration of (+/-)-buthionine sulphoximine (BSO), an inhibitor of glutamylcysteine synthetase. First, we determined the effects of BSO on hepatic and renal glutathione levels in the guinea pig. Guinea pigs (pigmented animals of both sexes or male albino animals) were killed at intervals up to 72 hr after i.p. administration of 1.6 g kg-1 BSO. Livers, and also kidneys in the case of pigmented guinea pigs, were removed and total glutathione (GSH + GSSG) measured. Glutathione levels reached a nadir in the liver at 24-48 hr (11% of control) and in the kidneys at 24 hr (14% of control) after administration of BSO. Hepatic but not renal levels approached control values by 72 hr. There were no sex or strain differences. Pigmented guinea pigs were anaesthetised and their endocochlear potential and a.c. cochlear potential in response to a 4 kHz tone were measured using an intracochlear microelectrode. The depression of these potentials by i.v. administration of 60 mg kg-1 EA was not affected by administration of 1.6 g kg-1 BSO 24 hr earlier, despite profound depletion of glutathione. Also prior p.o. administration of N-acetyl-L-cysteine did not affect hepatic glutathione levels nor modify the toxicity of EA. These results suggest that the acute cochlear toxicity of EA is not altered by glutathione depletion, a finding which argues against a role for the metabolic activation of EA in its ototoxicity.
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PMID:Glutathione depletion in the guinea pig and its effect on the acute cochlear toxicity of ethacrynic acid. 317 87

Thallous malonate was administered orally to hamsters in a single dose of 10 mg Tl/kg or 50 mg Tl/kg body weight. After 1 day and 3 days the levels of lipid peroxidation and non-protein sulfhydryls (NPSH) and glutathione peroxidase (GSH-Px) activity in tissues were measured. At a thallium dose of 10 mg/kg, increases in lipid peroxidation were already apparent in the kidney after 1 day. On the other hand, a marked increase in lipid peroxidation with decrease in NPSH content and GSH-Px activity in the kidney and liver were found 3 days after administration of the 50 mg Tl/kg dose, and renal and liver damage also developed. These results suggested that thallous malonate-induced tissue damage may be associated with the development of peroxidative processes caused by depression of GSH and inhibition of the GSH-Px activity-linked defensive system.
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PMID:Induction of lipid peroxidation in tissues of thallous malonate-treated hamster. 320 72

In previous studies, diethylmaleate (DEM)- and phorone-induced hepatic glutathione (GSH) depletion in rats was accompanied by impaired evolution of 14CO2 from the N-14C-labeled methyl groups of aminopyrine, which in turn was attributed to impaired generation of formaldehyde, its subsequent oxidation to formate, or to some combination of both. In the present study, l-buthionine sulfoximine (BSO)-induced hepatic GSH depletion was also accompanied by decreased evolution of CO2 from aminopyrine, but the extent of the fall in CO2 was less than that induced by DEM or phorone, even though the decrease in hepatic GSH was comparable with all three GSH-lowering compounds. Incubation of freshly prepared normal hepatic microsomes in vitro with the GSH-lowering agents resulted in impaired aminopyrine-N-demethylase (APDM) activity with inhibition by phorone greater than DEM greater than BSO. By contrast, hepatic microsomes prepared from rats pretreated with these compounds had normal APDM activity. 14CO2 evolution from i.p. administered [14C]formaldehyde was not impaired by any of the GSH-lowering compounds. Thus, assessment of APDM activity and formaldehyde metabolism did not unequivocally establish the mechanism(s) by which CO2 evolution from aminopyrine is depressed by DEM, phorone and BSO, although low GSH is likely to impair metabolism of formaldehyde formed in liver after demethylation of aminopyrine. Quantitative differences in the degree of depression of CO2 evolution suggest that at least DEM and phorone exert an additional inhibitory effect by a GSH-independent mechanism. This may involve inhibition of aminopyrine-N-demethylase activity.
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PMID:Effect of glutathione depletion on aminopyrine and formaldehyde metabolism. 335 87

The mechanism of increase in the inner membrane permeability induced by Ca2+ plus Pi, diamide and hydroperoxides has been analyzed. (1) The permeability increase is antagonized by oligomycin and favoured by atractyloside. The promoting effect of atractyloside is strongly reduced if the mitochondria are simultaneously treated with oligomycin. (2) Addition of the free-radical scavenger, butylhydroxytoluene, results in a complete protection of the membrane with respect to the permeability increase. (3) Although membrane damage and depression of the GSH concentration are often associated, there is no direct correlation between extent of membrane damage and concentration of reduced glutathione. Abolition of the permeability increase by butylhydroxytoluene or by oligomycin is not accompanied by maintenance of a high GSH concentration in the presence of diamide or hydroperoxides. The membrane damage induced by Ca2+ plus Pi is not accompanied by a depression of the GSH concentration. (4) It is proposed that a variety of processes causing an increased permeability of the inner mitochondrial membrane merge into some ultimate common steps involving the action of oxygen radicals.
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PMID:Permeability of inner mitochondrial membrane and oxidative stress. 340 79

The effects of administering indole-3-carbinol (I-3-C) on carbon tetrachloride (CCl4)-induced hepatotoxicity were examined. Mice received by gavage 0-150 mg I-3-C/kg body wt in methanol-extracted corn oil, followed 1 h later by 15 microliters CCl4/kg body wt in corn oil. Animals were sacrificed 24 h after receiving CCl4. Pretreatment with I-3-C reduced the degree of centrolobular necrosis, as observed histologically. Additionally, CCl4-mediated elevated serum enzymes were reduced by I-3-C. Although I-3-C induced elevated levels of cytochrome P-450 and associated mixed-function oxidase activity, the CCl4 depression of these parameters was not clearly reversed by I-3-C. However, CCl4 produced decreases in hepatic levels of glutathione (GSH), total reducing equivalents, and protein sulfhydryls, all of which were restored to control levels by I-3-C. Using mouse liver microsomes in an NADPH-fortified reaction mixture, I-3-C inhibited, in a concentration-dependent manner, CCl4-initiated lipid peroxidation, with 50% inhibition at 35-40 microM I-3-C. When mice were treated by gavage with 50 mg [14C]I-3-C/kg body wt, concentrations of radiolabel in the liver were greater than 100 microM after 1 hr. This was five times the level of radioactivity measured in blood and three times the concentration of I-3-C necessary for 50% inhibition of CCl4-mediated lipid peroxidation in vitro. The data are consistent with the hypothesis that I-3-C intervenes in CCl4-mediated hepatic necrosis by combining with reactive free radical metabolites of CCl4, thereby protecting critical cellular target sites.
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PMID:Protection against carbon tetrachloride hepatotoxicity by pretreatment with indole-3-carbinol. 355 31

The potential of dietary glutathione to alter immune response in aging mice was studied. Four (young), 17 (mature) and 24 (old) month old C57BL/6Nia male mice were fed semi-purified, nutritionally adequate diets containing 0 (control) to 1.0% of reduced glutathione (GSH) for 4 weeks. Concanavalin A (Con A) stimulated proliferation of splenocytes was assessed by [3H]thymidine incorporation. Delayed-type hypersensitivity (DTH) to dinitrofluorobenzene (DNFB) was measured by a radioisotopic method. Spleen GSH and splenocyte thiol (-SH) levels were determined by HPLC and N-ethyl[14C]maleimide binding, respectively. In the control fed group, mature and old mice showed 67% and 72% reductions (P less than 0.05) in Con A stimulated [3H]thymidine incorporation compared to young mice. Dietary GSH supplementation partially, but significantly (P less than 0.05) reversed this age-associated decline in mature and old mice. DTH assays revealed that the in vivo T-cell-mediated immune function is depressed with age and that dietary GSH supplementation reverses this depression. Spleens from control-fed mature and old mice contained 12 and 19% less GSH, respectively, than young mice (P less than 0.05). This decline was also reversed (P less than 0.05) by dietary GSH supplementation. Splenocyte -SH content after incubation with Con A and responsiveness to this mitogen were positively correlated in old mice and were greater (P less than 0.05) in GSH supplemented animals. Thus, dietary GSH supplementation improves the splenic status of this tripeptide and enhances T-cell mediated immune responses in aging mice.
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PMID:Reversal of age-associated decline in immune responsiveness by dietary glutathione supplementation in mice. 360 48

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

After subcutaneous injection of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) to rats, glutathione reductase activity in lung and liver diminished rapidly. The restoration of enzyme activity occurred more slowly in the lung than in the liver. The pattern for the time-course of total glutathione (GSH) levels was similar between lung and liver, except for a marked depression of hepatic levels 6 h after drug administration. The level of malondialdehyde (MDA) in lung was not affected by BCNU throughout the experimental period (3 days). However, the level in liver had increased significantly by 6 h after drug administration. These observations indicate that lipid peroxidation in lung was not induced by BCNU even when glutathione reductase activity was markedly diminished. In contrast, the lipid peroxidation in liver was induced by BCNU and was preceded by an early marked depression in total GSH.
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PMID:Effects of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) on the levels of glutathione and lipid peroxidation and the activity of glutathione reductase in liver and lung. 382 16

The disposition and disposal of the -SH groups of the lens during aging and cataractogenesis have been investigated by laser Raman spectroscopy as a noninvasive microprobe in the intact living lens. In this procedure -SH and -S-S- give unique discrete Raman signals (at 2580 and 508 cm-1) that may be used to calculate relative concentrations in a very small volume of the lens. We present evidence showing an unexpected and remarkable difference with respect to these groups between the mouse lens and the lenses of guinea pig and man. The mouse lens nucleus exhibits a precipitous fall in the -SH concentration on aging from 1 to 6 months; concomitantly, there is a rise in -S-S- of comparable magnitude, indicating a direct conversion. The guinea pig lens, however, is quite different with respect to the age-dependent change in nuclear -S-S-: there is none between 6 months and 5 years. In the human lens -S-S- behaves exactly as in the guinea pig lens: the level is low and does not change with age between 9 and 65 years. With respect to nuclear -SH, these two latter species of lenses show some decrease with age but nothing like the approach to zero found in the aging mouse lens nucleus. These differences involving lenticular -SH and -S-S- appear to be correlated with the hard nucleus in the mouse lens and the softer nuclei of lenses in guinea pigs and humans. The relatively high level of -S-S- in the old but clear mouse lens does not support the idea that protein aggregation involving formation of intermolecular -S-S- bonds is necessarily an important cause of nuclear cataract. The small but significant age-related depression of -SH in guinea pig lens nuclei without any accumulation of -S-S- may be explained as a result of glutathione (GSH) oxidation and subsequent extrusion of glutathione disulfide (GSSG) by the lens. We propose that the oxidation of glutathione proceeds by reaction with protein disulfide groups to yield protein sulfhydryl (PSH) and a mixed disulfide of glutathione and protein; the mixed disulfide is capable of being reduced by glutathione reductase and NADPH, yielding the original PSH and GSSG, which is extruded from the lens. It remains to be determined if this mechanism is more active in guinea pig and human lenses than in the mouse lens.
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PMID:Disulfide bond formation in the eye lens. 386 9


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