Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023380 (lethargy)
 5,697 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

2-Chloroacetaldehyde (CAA) formed during the metabolism of the anti-cancer drug ifosfamide (IP) has been implicated in ifosfamide-related neurotoxicity during chemotherapy but the neurotoxic mechanisms are unknown. We have found that IP (900 mg kg-1, p.o.) caused lethargy and mild hind limb paralysis after 6 h. Neurotoxicity and IP-induced mortality was markedly enhanced in mice pretreated with either phenobarbital or dexamethasone to induce cytochrome P4503A. Cerebral glutathione (GSH) levels were also markedly depleted in these pretreated mice. 2-Chloroethanol (92 mg kg-1, i.p.) (CE) also caused a 50% reduction in cerebral GSH 6 h after administration to mice. At this time maximum lethargy and unresponsiveness to touch was apparent in CE-treated mice. Severe hind limb paralysis developed and death ensued 12-18 h later. Prior depletion of cerebral GSH with 2-cyclohexene-1-one greatly accelerated the onset of CE-induced neurotoxicity suggesting that cerebral GSH status is an important determinant of CE-induced neurotoxicity. Furthermore, pretreatment with N-acetylcysteine delayed both CE-induced neurotoxicity and cerebral GSH depletion. Induction of cerebral but not hepatic CYP2E1 by ethanol before CE challenge also potentiated CE-induced cerebral GSH depletion and neurotoxicity. Hepatic GSH depletion was unaffected suggesting that CE-induced paralysis is dependent on a cerebral but not a hepatic CYP2E1 catalysed oxidation of CE to CAA. Ethanol was neuroprotective even if given 60 min after CE and prevented further cerebral GSH depletion. 4-Methylpyrazole, a CYP2E1 and alcohol dehydrogenase inhibitor, prevented both CE-induced hepatic and cerebral GSH depletion and paralysis. This suggests that the neurotoxicity associated with IP chemotherapy involves activation of chloroethanol by cerebral CYP2E1 to chloroacetaldehyde which mediates cerebral GSH depletion. Neurotoxicity may be prevented by restoring cerebral GSH status and/or by preventing activation of CE by CYP2E1 with ethanol.
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PMID:2-Chloroacetaldehyde-induced cerebral glutathione depletion and neurotoxicity. 876 99

A series of 1-(di)halo-2-fluoroethanes reported in the literature to be nontoxic or of low toxicity were found to be highly toxic by the inhalation route. Experiments were performed that showed the compounds, 1,2-difluoroethane, 1-chloro-2-fluoroethane, 1-chloro-1,2-difluoroethane, and 1-bromo-2-fluoroethane to be highly toxic to rats upon inhalation for 4 hr. All four compounds had 4-hr approximate lethal concentrations of < or = 100 ppm in rats. In contrast, 1,1-difluoroethane (commonly referred to as HFC-152a) has very low acute toxicity with a 4-hr LC50 of > 400,000 ppm in rats. Rats exposed to the selected toxic fluoroethanes showed clinical signs of fluoroacetate toxicity (lethargy, hunched posture, convulsions). 1,2-Difluoroethane, 1-chloro-2-fluoroethane, 1-chloro-1,2-difluoroethane, and 1-bromo-2-fluoroethane were shown to increase concentrations of citrate in serum and heart tissue, a hallmark of fluoroacetate intoxication. 19F NMR analysis confirmed that fluoroacetate was present in the urine of rats exposed to each toxic compound. Fluorocitrate, a condensation product of fluoroacetate and oxaloacetate, was identified in the kidney of rats exposed to 1,2-difluoroethane. There was a concentration-related elevation of serum and heart citrate in rats exposed to 0-1000 ppm 1,2-fluoroethane. Serum citrate was increased up to 5-fold and heart citrate was increased up to 11-fold over control citrate levels. Metabolism of 1,2-difluoroethane by cytochrome P450 (most likely CYP2E1) is suspected because pretreatment of rats or mice with SKF-525F, disulfiram, or dimethyl sulfoxide prevented or delayed the toxicity observed in rats not pretreated. Experimental evidence indicates that the metabolism of the toxic fluoroethanes is initiated at the carbon-hydrogen bond, with metabolism to fluoroacetate via an aldehyde or an acyl fluoride. The results of these studies show that 1-(di)halo-2-fluoroethanes are highly toxic to rats and should be considered a hazard to humans unless demonstrated otherwise.
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PMID:Fluoroacetate-mediated toxicity of fluorinated ethanes. 881 68