摘要:

Two alternatives for the treatment of lead intoxication, administration of zinc or a thiol donor, S‐adenosyl‐L‐methionine (SAM), were analysed. Rats were exposed to lead (Pb)‐acetate (60 mg/1) in drinking water during 90 days; one group also received SO4Zn in water (40 mg/l), while another received both Pb and SAM (5 mg/24 hr intraperitoneally. Erythrocytic δ‐aminolaevulinic dehydratase (ALA‐D) activity was significantly reduced (P<0.001) both in rats receiving Pb alone and in rats receiving Pb and each of the other two treatments. The high erythrocytic uroporphyrinogen synthetase (URO‐S) activity noticed in Pb administered rats, was significantly (P<0.001) reduced in animals treated either with zinc or with SAM. Hepatic ALA‐D activity tended to decrease while renal enzyme activity was not modified by the low level Pb exposure used in this work. Interestingly, SAM treated rats in both tissues exhibited significantly (P<0.01) higher activities of the enzyme. It is argued that SAM treatment causes a surplus of thiols that allows the full expression of ALA‐D

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1993.tb01562.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Exposure of male CBA mice to methyl mercuric chloride, CH3HgCl, (10–40 mg/1 in drinking water) for 2 weeks resulted in dose‐related Hg deposition and enhanced lipid peroxidation in liver, kidney and brain. Mice were fed well‐defined semisynthetic diets containing different levels of α‐tocopherol (10, 100 or 1000 mg/kg) or β‐carotene (1000, 10000 or 100000 IU/kg) for four weeks, two groups on each diet. The concentrations of α‐tocopherol and β‐carotene used corresponded to deficient, normal and high levels. During the last two weeks, one group on each diet was given 40 mg CH3HgCl/1 of drinking water. High dietary α‐tocopherol protected against CH3HgCl induced hepatic lipid peroxidation, whereas the α‐tocopherol deficient diet further enhanced CH3HgCl induced hepatic lipid peroxidation. Similar, though statistically non‐significant effects occured in the kidneys, α‐Tocopherol did not protect against CH3HgCl induced lipid peroxidation in the brain. Excess dietary β‐carotene further enhanced CH3HgCl induced lipid peroxidation in liver, kidney and brain. CH3HgCl significantly decreased the activity of total glutathione peroxidase (T‐GSH‐Px) and Se‐dependent glutathione peroxidase (Se‐GSH‐Px) in the kidneys in all dietary groups. High dietary α‐tocopherol enhanced the activity of Se‐GSH‐Px in liver and kidney compared to the activity in mice fed the normal level of α‐tocopherol. This occured in mice exposed to CH3‐HgCl as well as in unexposed mice, and the difference between CH3HgCl exposed and unexposed mice was not diminished. High dietary α‐tocopherol increased the activity of both Se‐GSH‐Px and T‐GSH‐Px in the brain of CH3HgCl‐exposed mice. The dietary level of β‐carotene did

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1993.tb01563.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Memantine, an amantadine derivative, is therapeutically used for the treatment of various neurological and psychiatric disorders such as Parkinson's disease, spasticity, and dementia. Pharmacokinetics of memantine and its effects on phospholipid content and composition, on membrane properties and functions such as fluidity and β‐adrenergic transmission were studied in cultured human fibroblasts and macrophages. The kinetic behaviour of memantine was characteristic for a lysosomotropic drug. Fibroblasts exposed to14C‐memantine in the μM range accumulated the drug up to 200 fold above initial medium concentrations. Lysosomal drug storage was proven by indirect evidence and by analyses of subcellular fractions. Repetitive exposure to memantine resulted in a cumulative uptake. While memantine uptake after single exposure was fully reversible, the rate and extent of release of chronically accumulated drug was reduced but could be enhanced by the addition of unlabelled memantine or ammonium chloride to the medium. Chronic, but not single, exposure to memantine above 10 μM resulted in a concentration dependent phospholipid accumulation and in a shift in the phospholipid composition. There was an overproportionate increase in phosphatidylinositol at the expense of phosphatidylserine and sphingomyelin. Chronic exposure of cultured cells to memantine increased fluidity in the superficial layers of the plasma membrane and reduced the isoproterenol‐stimulated cAMP‐response without affecting β‐adrenoceptor density. All these findings were compatible with the kinetic behaviour and the effectiveness expected of a weak lysoso

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1993.tb01564.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Effect of cadmium (1 mg/kg body weight) and ethanol (2 g/kg body weight) exposure, alone as well as in combination, on essential trace metal homeostasis, lipid peroxidation and antioxidant defense enzymes in various regions of the adult rat brain was investigated. It was observed that cadmium when administered alongwith ethanol accumulated significantly in corpus striatum (3.5 fold) and cerebral cortex (3.0 fold) compared to the cadmium treated group. The ethanol induced accumulation of cadmium led to significant depletion in the levels of essential trace metals like zinc and copper in these regions of the brain. Further, cadmium or ethanol alone did not show any significant effect on lipid peroxidation and antioxidant defense enzymes in any of the regions of the adult brain but when given in combination, caused a significant increase in lipid peroxidation and markedly decreased the activities of antioxidant defense enzymes like glutathione peroxidase, superoxide dismutase and catalase particularly in corpus striatum and cerebral cortex. Structural alterations produced by increased lipid peroxidation after cadmium and ethanol co‐exposure may have profound effect on the activities of membrane bound enzymes and hence may lead to functional impairment. The results of the present study imply that ethanol renders the adult brain more susceptible to the neurotoxic effects of cadmium. Corpus striatum and cerebral cortex are more vulnerable to the toxic effects of cadmium under the influence of ethanol than other regions of the brai

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1993.tb01565.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

The aim of the present study was to examine the effects of the hepatotoxic drug, acetaminophen, on the synthesis rates of glutathione, activated sulphate (PAPS, adenosine 3′‐phosphate 5′‐phosphosulphate) and the acetaminophen metabolites, acetaminophen‐glutathione and acetaminophen‐sulphate after inhibition of cytochrome P‐450 drug oxidation by cimetidine in isolated rat hepatocytes. The synthesis rates of glutathione and PAPS were determined simultanously by an established method based on trapping of radioactivity (35S) in the prelabelled glutathione and PAPS pools. Preincubation of the hepatocytes with 60 μg/ml cimetidine for 30 min. did not affect PAPS (1.71 versus 1.78 nmol/106cells) nor glutathione concentration (16.0 versus 16.4 nmol/106cells). The subsequent incubation with 5 mM acetaminophen resulted in decreased PAPS synthesis in the cimetidine treated cells [0.79 × 103versus 0.92 × 103nmol/(106cells · hr)] (P<0.05). There was no difference in PAPS concentration or acetaminophen‐sulphate synthesis [1.73 versus 1.79 nmol/106cells and 13.0 versus 12.9 nmol/(106cells · hr), respectively]. Decreased PAPS synthesis may be related to decreased ATP supply or may be the result of a feed‐back regulation due to diversion of sulphur from glutathione synthesis to sulfoxidation. The glutathione synthesis was not significantly affected by cimetidine treatment [57 × 103versus 27 × 103nmol/(106cells · hr)]. As expected acetaminophen‐glutathione synthesis decreased by 38% [1.66 versus 2.68 nmol/ (106cells · hr)] (P<0.01). Also the glutathione concentration was lower in cimetidine treated cells [15.2 versus 15.9 nmol/ 106cells] (P<0.05). We have previously shown that glutathione synthesis was reduced if substrate availability decreased (acetaminophen concentration lowered). Thus, the unaltered glutathione synthesis observed in the present study in which N‐acetyl‐p‐benzoquinoneimine formation was diminished suggests that cimetidine does not inhibit all acetaminophen metabolites

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1993.tb01566.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

The localization of the thermogenic effect of ephedrine (1 mg · kg‐1infused intravenously over 10 min.) was studied in 6 fasted dogs anaesthetized with etorfin‐acepromazin‐N2O. Three experiments were performed in each animal to determine the effect of ephedrine on a) splanchnic oxygen uptake, b) lower leg oxygen uptake and c) the work of the heart. In all experiments whole body oxygen uptake was monitored. Following ephedrine administration the following significant changes were seen as whole body oxygen uptake increased 16%, and splanchnic and lower leg oxygen uptakes increased respectively from 38.4 to 42.3 and from 7.3 to 12.1% of the whole body control oxygen uptake. The pressure‐volume work of the heart more than doubled. Significant changes were also seen in mean arterial blood pressure, pulse rate, cardiac output, splanchnic blood flow, and haematocrit and haemoglobin concentration. Plasma glycerol and free fatty acid concentrations increased after ephedrine, and the effects were not elicited by circulating catech

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1993.tb01567.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Dihydroergocryptine is a hydrogenated ergot derivative with pharmacological actions mainly related to its dopaminomimetic activity. Here we report that dihydroergocryptine can protect cultured rat cerebellar granule cells against glutamate‐induced neurotoxicity, assessing cell viability with the fluorescein diacetate‐propidium iodide technique. Dihydroergocryptine antagonized both the neuronal death produced by acute exposure to a toxic glutamate concentration as well as the normal age‐dependent degeneration in culture. The effect of dihydroergocryptine might be mediated by a scavenger action as suggested by the fact that the compound in a concentration‐dependent manner reduced the formation of intracellular peroxides produced in cerebellar granule cells by exposure to 100 μM glutamate. This action is apparently not mediated entirely by interactions with the dopamine D2receptors. The neuroprotective action suggests that dihydroergocryptine might be a potential useful drug in the therapy and/or prophylaxis of acute and chronic neurodegenerative diseases related to excitotoxi

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1993.tb01568.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Various strains of rats differ in their sensitivities towards benzodiazepines suggesting that variations in biological features are responsible for these differences. All reports concern inbred strains. We have studied male rats of three outbred Wistar strains with regard to the pharmacokinetics of desmethyldiazepam given as a single intravenous dose. The elimination half‐life of desmethyldiazepam was longer in the Riv:TOX(M) (from the National Institute of Public Health and Environmental Protection) and in the Cpb:WU strain than in the Crl:(WI)BR strain. This strain difference in elimination of desmethyldiazepam may be related to differences in liver enzyme activitie

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1993.tb01569.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Effects of either a single (300 mg/kg) or a subchronic (0.3 and 0.6% for 70 days) oral administration of a dithiocarbamate fungicide (zinc ethylene‐bis‐dithiocarbamate, zineb) on hepatic drug metabolism and on the activity of several glutathione‐dependent enzymes were investigated in male New Zealand White rabbits. While a pronounced reduction in the rate of oxidative biotransformations occurred after either single or repeated exposure, both cytochrome P450 and total haem content were lowered following acute challenge to zineb. None of the experimental protocols affected microsomal carboxylesterase but induced a marked increase in glutathione content and none of the examined glutathione‐dependent enzymes was altered by the single administration of zineb, whereas the subchronically exposed rabbits showed a fall in the activites of both total glutathione S‐transferase and selenium‐independent glutathione peroxidase. In the 0.6% treated animals, a decrease in class μ glutathione S‐transferase and glyoxalase I, and an increase in thiol‐transferase activities were also recorded. It is concluded that (1) zineb is able to selectively impair oxidative drug metabolism with possible different mechanism(s) according to the duration of the exposure, (2) only the subchronic treatment affects glutathione‐dependent enzymes, (3) the decrease in glutathione S‐transferase activity would seem to be ascribed to a direct interactio

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1993.tb01570.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1993.tb01571.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY