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PubMed1999

Enhanced quinone reductase (QR) activity correlates with promotion potential of diethyl maleate (DEM) in rat forestomach and glandular stomach carcinogenesis initiated with N-methyl-N'-nitrosoguanidine (MNNG).

The modifying effect of diethyl maleate (DEM) on gastric tumor development was studied in rats initially given N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and hypertonic sodium chloride (H-NaCl 10% or 5%). Groups of animals were maintained with or without a 0.2% DEM dietary supplement after treatment with MNNG and H-NaCl and sacrificed at week 20. Forestomachs and livers cytosolic NAD(P)H:quinone-acceptor oxidoreductase (QR) activity was also analyzed. The incidences of forestomach severe hyperplasias in the MNNG + H-NaCl --> DEM groups were also significantly higher than in the MNNG + H-NaCl alone group (P < 0.01 and P < 0.05 for 5% and 10% groups, respectively). Similarly, in the glandular stomach, the numbers of preneoplastic pepsinogen 1 altered pyloric glands (PAPGs) in the MNNG + H-NaCl --> DEM groups were significantly increased (P < 0.01 for both concentrations). The QR activities in the groups treated with DEM showed 2- to 3-fold increases as compared with the control level. The results indicate that treatment with 0.2% DEM after MNNG initiation exerts enhancing effects on both forestomach and glandular stomach carcinogenesis. Induction of QR, a Phase II enzyme, activity in the rat stomach by DEM may be associated with promotion of stomach carcinogenesis rather than inhibition.

Animals↗
PubMed1997

Cholecystokinin B receptor antagonists enhance the locomotor response to the N-methyl-D-aspartate antagonists phencyclidine and dizocilpine maleate.

The cholecystokinin antagonists L-740,093, L-365,260, LY-288513 and CI988, which are all selective for the cholecystokininB receptor subtype, were examined for their ability to modulate locomotor activity induced by the non-competitive N-methyl-D-aspartate receptor antagonists phencyclidine and dizocilpine maleate (MK-801) in habituated rats. It was found that the locomotor effects (motility, locomotion) produced by subcutaneous administration of phencyclidine (2 mg/kg) were significantly potentiated by intraperitoneal (i.p.) administration of L-740,093 (1 mg/kg), L-365,260 (10 mg/kg), LY-288513 (10 mg/kg), but not CI-988 (10 mg/kg). Locomotor activity induced by subcutaneous administration of MK-801 (0.15 mg/kg) was potentiated by intraperitoneal L-740,093 (0.3, 1 and 3 mg/kg). L-740,093, L-365,260, LY-288513 and CI-988 administered alone did not alter spontaneous locomotor activity (motility) as compared to vehicle/saline controls. However, when these antagonists were administered to naive, unhabituated rats, L-365,260 and LY-288513 caused a significant reduction in motility compared to the vehicle control. These findings suggest that, although cholecystokinin may be involved in exploratory behaviour exhibited by rats in a novel environment (unhabituated rats), its role is negligible in rats subjected to a familiar environment (habituated rats). Furthermore, these results support the interpretation that cholecystokinin has a suppressant effect on locomotion elicited by phencyclidine and MK-801, and that this inhibitory action of cholecystokinin is mediated via the cholecystokininB receptor, since it can be eliminated by administration of cholecystokininB antagonists. It is suggested that the site of action of the cholecystokininB receptors involves mainly the cholecystokinin/glutamate projection from the cortex to the anterior nucleus accumbens and/or striatum. Finally, the present study provides two examples of endogenous release of a neuropeptide resulting in behavioural consequences.

Animals↗
PubMed1997

Dizocilpine maleate, an N-methyl-D-aspartate antagonist, inhibits dipsogenic responses and C-Fos expression induced by intracerebral infusion of angiotensin II.

The interactions between dizocipline, an N-methyl-D-aspartate open channel antagonist, and the induction of water drinking and c-fos expression by intracerebroventricular (i.c.v.) infusion of angiotensin II have been studied. Pretreating male rats with i.c.v. dizocilpine maleate (100 or 300 nmol) or tenocyclidine (150 nmol), both non-competitive N-methyl-D-aspartate antagonists, inhibited the subsequent dipsogenic response to i.c.v. angiotensin II (125 or 50 pmol, 5-10 min later). Dizocilpine also decreased the angiotensin II-evoked expression of c-fos in the median preoptic nucleus, supraoptic nucleus and the medial (parvicellular) and lateral (magnocellular) parts of the hypothalamic paraventricular nucleus, as well as in the nucleus of the solitary tract and the lateral parabrachial nucleus. Double staining showed that suppression of c-fos expression occurred in N-methyl-D-aspartate R1 receptor containing neurons in the hypothalamus. Pretreating rats with any of three competitive glutamate antagonists (2-amino-5-phosphonopentanoic acid, 60 or 160 nmol; gamma-D-glutamylglyine, 400 nmol; (DL-3/(R)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid, 0.1 nmol) or the glycine site antagonist 7-chlorokynurenic acid had no effects on angiotensin II-induced drinking. Neither did pretreating rats with the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid antagonist 6-cyano-7-nitroquinoxaline-2,3-dione [two infusions, 30 min (240 nmol) and 5 min (160 nmol) before angiotensin II]. To eliminate cross-reactivity of dizocilpine with nicotinic receptors, animals were pretreated with nicotinic acetylcholine blocker mecamylamine (250 nmol, i.c.v.), but this had no effect on angiotensin II-dependent drinking or c-fos expression. These results suggest that an N-methyl-D-aspartate-type glutamate receptor is implicated in the dipsogenic and cellular responses to i.c.v. angiotensin II, and point to the existence of a novel set of interactions between excitatory amino acids and this neuropeptide.

Angiotensin II↗
PubMed1999

Dizocilpine maleate, MK-801, but not 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline, NBQX, prevents transneuronal degeneration of nigral neurons after neurotoxic striatal-pallidal lesion.

Unilateral neurotoxin lesion of rat caudate-putamen and globus pallidus resulted in delayed, transneuronal degeneration of GABAergic substantia nigra pars reticulata neurons. To explore whether the disinhibition of endogenous glutamate excitatory input played a role in the degeneration of substantia nigra pars reticulata neurons, animals with unilateral striatal-pallidal lesions received three daily intraperitoneal injections of either dizocilpine maleate (MK-801, 1 or 10 mg/kg), an N-methyl-D-aspartate glutamate receptor blocker, or 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX, 30 mg/kg), an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor blocker, that began 24 h after the striatal-pallidal neurotoxin lesion. Drug treatment affected neither the volume of the initial lesion nor the volume of striatal-pallidal glial fibrillary acidic protein immunoreactivity. Neuron number in the substantia nigra pars reticulata ipsilateral to the lesioned striatopallidum was reduced on average by 37% in untreated control rats, in low dose MK-801, and NBQX-treated rats (P<0.0001). However, in animals treated with high doses of MK-801 there was no difference in the number of neurons in the substantia nigra pars reticulata ipsilateral or contralateral to the neurotoxin lesion. These data demonstrate that dose-related treatment with N-methyl-D-aspartate glutamate receptor blockers protects substantia nigra pars reticulata neurons, and suggests that glutamatergic mechanisms play a role in delayed transneuronal degeneration.

Animals↗
PubMed2002

Altered responses to dizocilpine maleate administration in ethanol-withdrawn male and female rats.

Dizocilpine maleate (MK-801) is a highly potent, noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. Although it has been suggested that dizocilpine may be beneficial in alleviating some symptoms of ethanol withdrawal, a rigorous evaluation of beneficial versus detrimental (phencyclidine-like) actions has not been done. The objective of the present investigation was to explore whether dizocilpine protects against ethanol withdrawal-induced increases in seizure susceptibility without being compromised by its phencyclidine-like behavioral actions. The effects of dizocilpine were assessed by using seizure threshold determinations and scoring of open field behaviors. Low dose dizocilpine administration preferentially protected against bicuculline seizure induction in ethanol-withdrawn female rats when compared with findings in ethanol-withdrawn male rats. In contrast, we found dramatic reductions in dizocilpine-induced open field behaviors during ethanol withdrawal in both male and female rats compared with findings for pair-fed control animals. [3H]MK-801 binding analysis ruled out changes in cerebral cortex or hippocampus receptor density or affinity as having a primary role in these differential responses. Taken together, our findings from these studies indicate that there are complex neuroadaptations in NMDA receptor systems after persistent ethanol exposure, manifested as either enhanced or reduced responses, depending on the measure used.

Animals↗
PubMed2003

Effects of ethanol or rimcazole on dizocilpine maleate-induced behaviors in male and female rats.

The current investigation was undertaken to explore further the interactions between ethanol and the phencyclidine analog dizocilpine maleate (MK-801) on behaviors in male and female rats. It was previously found that ethanol dependence conferred cross-tolerance to the behaviorally activating effects of dizocilpine. The current set of studies was designed to assay the interactions between dizocilpine and ethanol in ethanol-naive animals by measuring open field behaviors. I also tested interactions between dizocilpine and rimcazole, a sigma receptor antagonist. In agreement with previous reports, I found significant effects of dizocilpine on several open field behaviors. In general, female rats displayed a lower level of hyperlocomotion and higher level of stereotypies than did male rats. Co-administration of ethanol delayed time to peak hyperlocomotion in male rats. It reduced locomotion in female rats compared with findings for administration of dizocilpine alone. Co-administration of ethanol with dizocilpine increased stereotypies in both sexes. Administration of ethanol increased locomotion to a greater degree in female than in male rats. In contrast, co-administration of rimcazole with dizocilpine had little effect on hyperlocomotion in male rats while increasing levels in female rats. Rimcazole increased dizocilpine-induced stereotypies to a greater extent in male than in female rats. Results of receptor-binding studies revealed small differences for cerebral cortical sigma receptors between male and female rats. Dizocilpine was unable to compete for sigma receptor-binding sites. This is in contrast to phencyclidine, which acts at both N-methyl-D-aspartate (NMDA) and sigma receptors. These findings extend previous evidence of interactions between ethanol and dizocilpine, but highlight that responses vary by measure, sex, and length of ethanol exposure. In addition, findings from the current study uncovered sex-selective interactions between dizocilpine and a sigma receptor ligand, providing further evidence for complex actions and interactions of this noncompetitive NMDA receptor antagonist with multiple sites in brain.

Animals↗
PubMed2002

Neuropharmacological profile of a novel potential atypical antipsychotic drug Y-931 (8-fluoro-12-(4-methylpiperazin-1-yl)- 6H-[1]benzothieno[2,3-b][1,5] benzodiazepine maleate).

The neuropharmacological profile of Y-931, 8-fluoro-12- (4-methylpiperazin-1-yl)- 6H-[1]benzothieno [2,3-b][1,5]benzodiazepine maleate, was investigated in comparison with those of typical and claimed atypical antipsychotic drugs. Similar to clozapine and olanzapine, Y-931 interacted with multiple neurotransmitter receptors such as dopaminergic, serotonergic, alpha-adrenergic, muscarinic and histaminergic receptors. Y-931, as well as the other antipsychotics, was active in a dose-dependent manner in established tests which are indicative of potential antipsychotic activity such as inhibition of apomorphine-induced hyperactivity and suppression of conditioned avoidance responses, however, only Y-931 and clozapine were devoid of cataleptogenic potential. In models of N-methyl-D-aspartate (NMDA) receptor hypofunction, Y-931 demonstrated the most potent protective action against the dizocilpine-induced neurotoxicity (neuronal vacuolization) in the rat retrosplenial cortex ([Y-931 (ED(50); 0.20 mg/kg, p.o.), olanzapine (1.1), clozapine (5.7), risperidone (6.9), haloperidol (19)). Furthermore, Y-931 and clozapine, unlike the other antipsychotics used, reversed the dizocilpine-induced social deficits at the same doses at which their neuroprotective action was exhibited. The present results suggest that Y-931 may be a novel potential atypical antipsychotic drug with a low risk of extrapyramidal syndrome (EPS) and the property to ameliorate NMDA receptor hypofunction.

Animals↗
PubMedDate not supplied

[Synthesis of monomoraprenyl- and monodolichylsuccinates and maleates].

The reactions of moraprenol and dolichol with succinic and maleic anhydrides in the presence of pyridine or triethylamine were studied, and the conditions were found for the efficient synthesis of moraprenyl and dolichyl hydrogen succinates and maleates. These may be of interest as analogues of moraprenyl and dolichyl hydrogen phosphates with modified anionic groups. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2004, vol. 30, no. 2; see also http://www.maik.ru.

Magnetic Resonance Spectroscopy↗
PubMed2002

Identification of sensitizing diethyleneglycol maleate in a two-component polyester cement.

Unsaturated polyester (UP) cement caused allergic contact dermatitis in car repair work. The resin was a condensate of polyols and maleic anhydride with reactive solvent, auxiliary substances, and inorganic reinforcement substances. To identify the causative chemicals, the cement was tested on a sensitized patient. For analysis, samples of the resin were eluted with acetone and eluted with hexane to precipitate inorganic material and large polyester molecules. The eluate was evaporated. The remainder, dissolved in acetone, was separated into fractions on silica plates by thin layer chromatography (TLC). On the developed (hexane/chloroform, 15/85) plates, 20 bands were obtained under UV-light at 254 nm. Samples of the bands were scraped and used for patch testing. The scraping at a retention factor (Rf) of 0.24 caused a skin reaction. The bands at this retention were removed from six plates, combined, eluted with acetone and purified again by TLC. The purified fraction mixed in petrolatum in the dilution series was used for conclusive patch testing on the patient. An allergic reaction was induced at down to 0.003% wt/wt. According to MS and IR analyses, the isolated compound was diethyleneglycol maleate (DEGM, MW204). In addition to the resin part, the sanding dust also contained this monomer.

Dermatitis, Allergic Contact↗
PubMed1990

The effects of dizocilpine maleate (MK-801), an antagonist of the N-methyl-D-aspartate receptor, on neurologic recovery and histopathology following complete cerebral ischemia in primates.

The present study was designed to determine if the noncompetitive excitatory amino acid antagonist, dizocilpine maleate, when administered after a 17 min period of complete cerebral ischemia in primates, would improve postischemic neurologic function and hippocampal histopathologic outcome when compared to placebo-treated animals. Ten pigtail monkeys were anesthetized and subjected to complete cerebral ischemia using an established neck tourniquet model. Five minutes postischemia, five monkeys received dizocilpine 300 micrograms/kg i.v. over 5 min, followed by an infusion of 150 micrograms/kg/h for 10 h. This produced plasma levels of the drug in excess of 30 ng/ml for the duration of the infusion. An additional five monkeys were treated with an identical volume of saline placebo. All monkeys received intensive care for the initial 24 to 48 h postischemia. At 96 h postischemia, there was no significant difference in neurologic function between the two groups (p = 0.53, with the placebo group having the numerically better outcome). There also was no significant difference between hippocampal histopathology scores between dizocilpine and placebo-treated monkeys. The authors conclude that dizocilpine is not an efficacious therapy in the treatment of neurologic injury that occurs following complete cerebral ischemia in this primate model.

Animals↗
PubMed1996

Glycine attenuates Fanconi syndrome induced by maleate or ifosfamide in rats.

It has become widely recognized that glycine (Gly) depletion predisposes isolated proximal tubules (PT) to necrotic cell damage induced by diverse insults and that Gly replacement in vitro is highly cytoprotective. However, the effectiveness of supplementation with Gly in vivo, where blood and tissue Gly normally are maintained at high levels, is incompletely defined. Our aim was to assess whether: (a) supplementation of Gly in drinking water of rats would attenuate the proximal tubule damage and the Fanconi syndrome (FS) induced by maleate (Mal), a classical proximal tubule toxin, or ifosfamide (IFO), an antineoplastic drug; and (b) to explore the mechanisms responsible for such effects, since Gly supplementation might be especially beneficial in treating the FS, where the kidney tends to waste amino acids. Rats received daily injection of Mal (2 mmol/kg) for two days without or with oral supplementation of 2% Gly. IFO, 50 mg/kg, was injected daily for five days without or with oral Gly. Control rats were injected with saline, without or with oral Gly. The results demonstrated that both Mal and IFO induced a FS characterized by wasting of amino and organic acids, glucose, and electrolytes, along with elevated plasma creatinine (Crn) and BUN, and decreased Crn clearance rate. Light microscopy revealed a necrotic lesion in the proximal tubules of the Mal group, but no necrosis after IFO. Gly strongly ameliorated the severity of renal necrosis and/or dysfunction induced by Mal or IFO, with significant decreases in total and fractional excretion of Na+, K+, PO4(3-) and glucose, decreased plasma BUN and Crn, and increased Crn clearance. Analysis of freeze-clamped cortical tissue showed substantial depletion of [Gly], [ATP] and [GSH] along with increased GSSG in Mal or IFO groups and correction of [Gly] and [ATP] with Gly supplementation, but no improvement with Gly of reduced gluthatione [GSH] or the ratio of reduced to oxidized gluthatione (GSH/GSSG). 31P-NMR analysis of the renal cortex indicated a decrease in Pi and various membrane phospholipids in Mal and IFO rats and prevention of this damage with Gly. These observations demonstrate that oral supplementation of Gly can provide protection against Mal or IFO-induced renal tubular cell dysfunction and structural damage. The lack of effect on glutathione oxidation and depletion suggests an action distal to toxin uptake and intracellular interactions, which is similar to the characteristics of Gly cytoprotection against diverse insults in vitro. The results also suggest modification by Gly of the primary toxicity of the agents and effects on phospholipid synthesis that could contribute to repair.

Administration, Oral↗
PubMed1971

The enzymic degradation of alkyl-substituted gentisates, maleates and malates.

1. Cell-free extracts, prepared from a non-fluorescent Pseudomonas grown on m-cresol, oxidized gentisate and certain alkyl-substituted gentisates with the consumption of 1 mol of oxygen and the formation of 1 mol of pyruvate from 1 mol of substrate. 2. In addition to pyruvate, malate was formed from gentisate; citramalate was formed from 3-methylgentisate and 4-methylgentisate; 2,3-dimethylmalate was formed from 3,4-dimethylgentisate. 3. One enantiomer, d-(-)-citramalate, was formed enzymically from 3-methylgentisate, 4-methylgentisate and citraconate. l-(+)-Citramalate was formed from mesaconate by the same extracts. When examined as its dimethyl ester by gas-liquid chromatography, enzymically formed 2,3-dimethylmalate showed the same behaviour as one of the two racemates prepared from the synthetic compound. 4. Maleate, citraconate and 2,3-dimethylmaleate were rapidly hydrated by cell extracts, but ethylfumarate and 2,3-dimethylfumarate were not attacked. 5. Cell extracts oxidized 1,4-dihydroxy-2-naphthoate to give pyruvate and phthalate. 6. Alkylgentisates were oxidized by a gentisate oxygenase (EC 1.13.1.4) present in Pseudomonas 2,5. The ring-fission products were attacked by maleylpyruvase, but not by fumarylpyruvase, and their u.v.-absorption spectra were those expected for alkyl-substituted maleylpyruvates. 7. When supplemented with ATP, CoA, succinate and Mg(2+) ions, an enzyme system from cells grown with 2,5-xylenol formed pyruvate from d- but not from l-citramalate. Extracts from cells grown with dl-citramalate or with itaconate attacked both d- and l-citramalate; other alkylmalates were cleaved in similar fashion to give pyruvate or 2-oxobutyrate. 8. These results accord with a general sequence of reactions in which the benzene nucleus of an alkylgentisate is cleaved to give an alkyl-substituted maleylpyruvate. The ring-fission products are hydrolysed to give pyruvate, plus alkylmalic acids which then undergo aldol fissions, probably as their CoA esters. In Pseudomonas 2,5 several homologous sequences of this general type appear to be catalysed by a single battery of enzymes with broad substrate specificities, whereas the metabolic capabilities of the fluorescent Pseudomonas 3,5 are more restricted. 9. Intact cells of both organisms metabolize d-malic acid by reactions that have not been elucidated, but are different from those which degrade alkylmalates.

Alkylation↗
PubMed2001

Efficacy and safety of intranasally applied dimetindene maleate solution. Multicenter study in children under 14 years suffering from seasonal allergic rhinitis.

The aim of this study was to investigate the efficacy and tolerability of intranasally applied dimetindene (CAS 3614-69-5) 0.1% spray in children suffering from seasonal allergic rhinitis. A total of 100 children under 14 years with acute seasonal allergic rhinitis participated in this randomised, single-blind, reference-controlled, multi-center, parallel group study with two treatment groups. The study took place between 2nd April and 16th September 1996 during the pollen season. Patients were examined at enrollment (day 1), day 8 and day 15. Patients kept diary throughout the 2-week treatment phase. Patients were randomised to receive either dimetindene 0.1% (Fenistil Nasal Spray) or a levocabastine (CAS 79516-68-0) 0.05% solution as reference medication. Both medications were supplied in similar outer packages. A single-blind approach was chosen, because the reference medication levocabastine requires two spray puffs per nostril as a single dose, whereas for dimetindene maleate solution a single spray puff per nostril is sufficient. Dimetindene 0.1% was applied with 1 spray puff (= 0.14 mg dimetindene) in each nostril and levocabastine with 2 spray puff (= 0.10 mg levocabastine) in each nostril every day in the morning before leaving the house and in the evening before going to bed. Additional administration of the spray was allowed up to 4 times a day if needed. Efficacy was assessed as change in severity of characteristic symptoms associated with pollen rhinitis: nasal rhinorrhea, nasal itching, nasal sneezing and nasal congestion. In addition, changes in ocular symptoms, lacrimation, ocular itching and red eyes, global physician's assessment of efficacy at the end of treatment were assessed. The primary criterion change of total nasal symptom severity score between day 1 and day 3 resulted in a statistically equivalent and therapeutically relevant symptom reduction for the two treatments. All secondary criteria showed a similar reduction in symptoms, thus underlining the consistency of the findings. Both nasal sprays were well tolerated. It is concluded from these results that dimetindene 0.1% nasal spray solution is a safe and efficient treatment option for children under 14 years suffering from seasonal allergic rhinitis.

Administration, Intranasal↗
PubMed1982

Effects of phospholipase A2 inhibitors on diethyl maleate-induced lipid peroxidation and cellular injury in isolated rat hepatocytes.

Isolated hepatocytes provide a suitable system for investigation of various aspects of the mechanism of a toxic response. The mechanism by which most chemicals induce hepatotoxicity is still not known. Evidence that phospholipases may play a role in cellular injury has been reported. In the present study the effects of reported inhibitors of phospholipase A2 (quinacrine, chlorpromazine, dexamethasone, and dibutyryl cyclic AMP) on diethyl maleate (DEM)-induced lipid peroxidation, reduced glutathione (GSH) depletion, and cellular injury were examined in isolated hepatocyte suspensions. Hepatocytes were incubated for 7 h under control conditions or with (1) DEM (4 mM), (2) one of the inhibitors (quinacrine, 10, 50, or 150 microM; chlorpromazine, 50 microM; dexamethasone, 0.1, 0.5, 1, or 2.5 mM; dibutyryl cyclic AMP, 0.1, 0.5, 1, or 2.5 mM) or aspirin (500 microM), or (3) a combination of DEM and one of the inhibitors or aspirin to determine their effect on DEM toxicity. Samples were withdrawn at hourly intervals for estimation of cellular injury (loss of intracellular K+ and lactate dehydrogenase and trypan blue exclusion index), lipid peroxidation (thiobarbituric acid reactants assay), and GSH concentration. Quinacrine and chlorpromazine inhibited DEM-induced lipid peroxidation but not cellular injury or GSH loss. This suggests that phospholipase A2 may be involved in DEM-induced lipid peroxidation but not cell damage. However, dexamethasone and dibutyryl cyclic AMP enhanced both lipid peroxidation and loss of cell viability due to DEM, suggesting novel aspects of the biochemical mechanisms of chemically induced cytotoxicity.

Animals↗
PubMed1989

Chloroform-induced multiple forms of ornithine decarboxylase: differential sensitivity of forms to enhancement by diethyl maleate and inhibition by ODC-antizyme.

The role of glutathione (GSH) and ornithine decarboxylase-antizyme (ODC-AZ) in the regulation of the chloroform-mediated stimulation of rat hepatic ornithine decarboxylase (ODC) was investigated. We have previously implicated roles for each while examining the chloroform effect on crude cytosolic enzyme preparations. In this study we examined the effect of pretreatment with diethyl maleate (DEM), a GSH-depleting agent, on the chloroform stimulation of the two forms of the rat hepatic ODC enzyme and the sensitivity of these two forms to inhibition by the ODC-AZ. While the pretreatment with DEM provided a greater amount of the two forms of the ODC enzyme, it also resulted in a differential stimulation of each form when compared to chloroform alone. Additionally, Peak II was 20-25% more sensitive to the same amount of ODC-AZ then Peak I ODC activity.

Animals↗
PubMed1990

Effects of 1,3-dichloropropene on the kidney of Fisher 344 rats after pretreatment with diethyl maleate, buthionine sulfoximine, and aminooxyacetic acid.

Acute nephrotoxicity of cis/trans-1,3-dichloropropene (DCP) was assessed in male Fisher 344 rats. Pretreatment of rats with corn oil, aminooxyacetic acid (AOA), buthionine sulfoximine (BSO), or diethyl maleate (DEM) was given intraperitoneally 1 h or 4 h prior to injection of DCP. Doses of DCP were 0, 25, 50, and 75 mg/kg intraperitoneally (4-5 animals per dose/pretreatment group). Urine was collected for 24 h. Excretion of creatinine, phosphorus, protein, N-acetylglucosaminidase (NAG), and the major metabolite of DCP, N-acetyl-S-(cis-3-chloroprop-2-enyl)-cysteine (3CNAC), was measured. Excretion of the metabolite, 3CNAC, increased in a dose-related manner from 0 to 50 mg/kg of DCP, but further increases were not seen at the 75 mg/kg dose. The pretreatments produced no alterations in the amounts of metabolite excreted when compared to corn oil controls. Zero-order metabolism or impaired metabolism is suggested to be occurring at high doses of DCP. The AOA pretreatment group showed no increase in the excretion of NAG, whereas other pretreatments (corn oil, BSO, DEM) showed elevations of NAG excretion at the highest DCP doses. AOA inhibits renal beta-lyase, an enzyme that mediates cleavage of mercapturic acid metabolites to toxic products. Since NAG excretion was not elevated in response to DCP with AOA pretreatment and was not raised by pretreatments that deplete glutathione, it is suggested that nephrotoxic effects of DCP may be mediated through the mercapturic acid metabolites on the kidney, rather than due to glutathione depletion per se.

Acetates↗
PubMed1978

Effects of diethyl maleate on aryl hydrocarbon hydroxylase and on 3-methyl-cholanthrene-induced skin tumorigenesis in rats and mice.

Topical administration of diethyl maleate (DEM) and L-methionine sulfoximine (MS) reduced the L-glutathione (GSH) levels in kidneys, livers, and skin of inbred BALB/c mice. Topical administration of DEM to BALB/c mice also increased the latency period before development of skin tumors that were induced by 3-methylcholanthrene painting. Similar treatment with MS also increased the latency period, though the delay was not as striking as that observed after DEM administration. Furthermore, DEM, which was believed to be specific in its action in reducing tissue GSH, was also capable of inhibiting aryl hydrocarbon hydroxylase (AHH) both in vitro and in vivo. Cyclohexene sulfide, another "specific" inhibitor of GSH transferase, inhibited AHH activity as well. Accordingly, the blockade of AHH by DEM may have been partly responsible for the increased latency time in the skin tumorigenesis experiments.

Animals↗
PubMed1982

Disulfiram-like effect of diethyl maleate on barbiturate-induced hypnosis and 5-hydroxytryptamine metabolism.

Diethyl maleate (DEM, 600 mg kg-1 i.p.) significantly potentiated hexobarbitone hypnosis and lowered plasma hexobarbitone level on awakening. Sleeping time following intracerebroventricular (i.c.v.) injection of phenobarbitone was also prolonged by DEM treatment. When administered to DEM-treated rats, L-tryptophan (50 mg kg-1 i.p.) significantly potentiated hexobarbitone hypnosis, although alone it had no effect in control rats. DEM markedly diminished the activity of brain low-Km aldehyde dehydrogenase (A1DH) and the formation of 5-hydroxyindoleacetic acid from 5-hydroxytryptamine (5-HT) without affecting MAO activity in various areas of the brain. Conversely, the protein-bound radioactivity derived from i.c.v. [14C]-5-HT was increased by DEM treatment. These results showed that DEM is comparable with disulfiram, a brain A1DH inhibitor, in terms of its effect on 5-HT metabolism and barbiturate hypnosis.

Aldehyde Dehydrogenase↗