UMLS:C0011570 - FACTA Search

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Query: UMLS:C0011570 (depression)
172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In vitro studies have shown that acetaldehyde is a more potent inhibitor of testicular steroidogenesis than ethanol. The present study examined the in vivo role of acetaldehyde in ethanol-induced reduction of testosterone by (1) determining the levels of acetaldehyde to which the testes were exposed subsequent to acute ethanol administration to mice; and (2) examining the effect of ethanol on testosterone in animals subsequent to drug pretreatment which decreased or increased ethanol-derived acetaldehyde. Ethanol-induced (3 g/kg) depression of testosterone was dependent upon gonadotropin stimulation. The increase in hCG-induced testosterone was suppressed (P less than 0.01) in ethanol- as compared to saline-treated animals [39.8 +/- 2.6 (S.E.M.) vs 28.1 +/- 2.3 ng/ml]. Pargyline (100 mg/kg) or cyanamide (8.4 mg/kg) increased (P less than 0.05) plasma and testicular acetaldehyde, while having no effect on the testosterone response to ethanol. Similarly, 4-methylpyrazole (25 mg/kg) reduced blood and testicular acetaldehyde to nondetectable levels, while having no effect on testosterone. Testicular acetaldehyde was lower (P less than 0.001) than plasma levels (14 +/- 2 vs 2.0 +/- 0.2 microM). This functional blood-testis barrier to acetaldehyde could be explained by testicular aldehyde dehydrogenases in the mitochondria (Km for acetaldehyde = 1.5 microM) and in the cytosol (Km = 123 microM) whose maximal activities totaled to more than 25-fold greater than that of testicular alcohol dehydrogenase (ADH). ADH was concentrated in the Leydig cells, while aldehyde dehydrogenase was evenly distributed in the testis. Ethanol prevented further hCG-induced rises in testosterone rather than inhibiting testosterone production to below pre-ethanol values. The above data argue against a significant role of acetaldehyde in the in vivo response of testosterone to ethanol. Ethanol appears to impair gonadotropin-testicular receptor interaction in vivo.
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PMID:Demonstration of a functional blood-testis barrier to acetaldehyde. Evidence for lack of acetaldehyde effect on ethanol-induced depression of testosterone in vivo. 397 44

The DNA segments containing the ADR1 gene and a mutant allele, ADR1-5c, have been isolated by complementation of function in Saccharomyces cerevisiae. The ADR1 gene is required for synthesis of the glucose-repressible alcohol dehydrogenase (ADHII) when S. cerevisiae cells are grown on a nonfermentable carbon source, whereas the ADR1-5c allele allows ADHII synthesis even during glucose repression. A plasmid pool consisting of yeast DNA fragments isolated from a strain carrying the ADR1-5c allele was used to transform a strain containing the adr1-1 allele, which prevents ADHII depression. Transformants were isolated which expressed ADHII during glucose repression. A plasmid isolated from one of these transformants was shown to carry the ADR1-5c allele by its ability to integrate at the chromosomal adr1-1 locus. The wild-type ADR1 gene was isolated by colony hybridization, using the cloned ADR1-5c gene as a probe. The ADR1-5c and ADR1 DNA segments were indistinguishable by restriction site mapping. A partial ADR1 phenotype could be conferred by a 1.9-kilobase region, but DNA outside of this region appeared to be necessary for normal activation of ADHII by the ADR1 gene.
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PMID:Isolation and characterization of the positive regulatory gene ADR1 from Saccharomyces cerevisiae. 634 14

In order to assess the process of oxidation and conjugation involved in biotransformation of vinyl chloride (VC), rats were exposed to 50, 200, 500, 1000 and 20,000 ppm inhaled VC. The rate of urinary excretion of thiodiglycollic acid (TDGA) after exposure to each investigated concentration of VC depends on the activity of microsomal monooxygenase. In general, higher levels of TDGA in urine were reflected by a more significant depression of non-protein sulfhydryl content in the liver of rats, whereas no changes were observed in those with inhibited activity of microsomal monooxygenase and depressed urinary levels of TDGA. The significance of alcohol dehydrogenase in the metabolism of low concentrations of VC has not been confirmed. Metabolism of VC in the range of 50--2 000 ppm is mediated by microsomal monooxygenase followed by conjugation with thiols.
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PMID:Urinary excretion of thiodiglycollic acid and hepatic content of free thiols in rats at different levels of exposure to vinyl chloride. 700 10

4-Methylpyrazole (4-MP), an alcohol dehydrogenase inhibitor, was administered to dogs to treat ethylene glycol (EG) intoxication. Eleven dogs were given 10.6 g of EG/kg of body weight; 5 dogs were treated with 4-MP 5 hours after EG ingestion and 6 dogs were treated with 4-MP 8 hours after EG ingestion. 4-Methylpyrazole was administered IV as a 50-mg/ml [corrected] solution in 50% polyethylene glycol: initial dose, 20 mg/kg; at 12 hours after initial dose, 15 mg/kg; at 24 hours after initial dose, 10 mg/kg; and at 30 hours after initial dose, 5 mg/kg. Physical, biochemical, hematologic, blood gas, serum and urine EG concentrations, and urinalysis findings were evaluated at 0, 1, 3, 6, 9, 12, 24, 48, 72 hours, and at 1 week and 2 weeks after EG ingestion. Dogs of both groups developed clinicopathologic signs associated with EG intoxication, including CNS depression, hyperosmolality, high anion gap metabolic acidosis, polydipsia, polyuria, calcium oxalate monohydrate and dihydrate crystalluria, and isosthenuria. Fractional excretion of sodium was increased in all dogs between 1 and 9 hours after EG ingestion, but remained increased beyond 24 hours only in the 2 dogs treated at 8 hours after EG ingestion that developed acute renal failure. All dogs treated 5 hours after EG ingestion recovered without morphologic, biochemical, or clinical evidence of renal impairment. Of the 6 dogs treated 8 hours after EG ingestion, 2 developed acute renal failure. One of the dogs treated 8 hours after EG ingestion remained isosthenuric for 2 months, but did not manifest any other signs of renal impairment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Efficacy of 4-methylpyrazole for treatment of ethylene glycol intoxication in dogs. 788 24

The inhibition of glycolysis during ethanol oxidation has been examined in isolated hepatocytes from fasted rats. Glycolytic flux was measured by determining the rate of release of tritium from [6-3H]glucose. During ethanol oxidation, the rate of glycolysis was inhibited 80% in freshly prepared hepatocytes, in which shuttle intermediates are depleted, but was depressed only about 20% in the presence of asparagine, a condition under which activity of the malate/aspartate shuttle was restored to normal levels. The inhibition of glycolysis was also partially released by addition of pyruvate and when alcohol dehydrogenase activity was depressed by 4-methylpyrazole. Titrations with this inhibitor revealed inverse linear relationships between the rates of glycolysis and ethanol oxidation. For any given rate of ethanol oxidation, glycolytic flux was lowest and the [lactate]/[pyruvate] ratio highest in the presence of aminooxyacetate, an inhibitor of the malate/aspartate shuttle, whereas flux was highest and the ratio lowest in the presence of asparagine. During these titrations with 4-methylpyrazole the inhibition of ethanol oxidation and concomitant restoration of glycolysis were accompanied by a decline in the [lactate]/[pyruvate] ratio, a substantial fall in the rate of reducing-equivalent transfer from cytoplasm to mitochondria and an increase in lactate accumulation. These findings imply that the reducing equivalents generated during ethanol oxidation compete with those arising in glycolysis for transfer to the mitochondria. This competition leads to an inhibition of aerobic glycolysis, and at the same time contributes to a rise in cytoplasmic NADH and fall in NAD+ that results in depression of anaerobic glycolysis. Allosteric inhibition of 6-phosphofructo-1-kinase due to a decrease in the concentration of fructose 2,6-bisphosphate did not appear to play a primary role in the inhibition of glycolysis by ethanol. Ethanol oxidation had no effect on glucose phosphorylation as measured with [2-3H]glucose, but induced a substantial increase in cycling between glucose and glucose 6-phosphate.
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PMID:The capacity of reducing-equivalent shuttles limits glycolysis during ethanol oxidation. 795 70

Toluene and its metabolites have been studied with respect to their reactive oxygen species-enhancing potential in isolated systems and in vivo. The induction of reactive oxygen species (ROS) production was assayed using the probe 2',7'-dichlorodihydrofluorescin diacetate (DCFH-DA). Intraperitoneal injection of toluene, benzyl alcohol or benzaldehyde caused a significant elevation in the rate of ROS formation within hepatic mitochondrial fractions (P2). In the brain, only toluene induced ROS formation, while benzyl alcohol and benzaldehyde did not have any effect. Glutathione (GSH) levels were depressed in liver and brain regions from toluene-treated rats. However, no such depression was evident in brains treated with toluene metabolites. P2 fractions from phenobarbital-pretreated rats exhibited a heightened ROS response when challenged with toluene, in vitro. Pretreatment of rats in vivo with 4-methylpyrazole, an alcohol dehydrogenase inhibitor, or sodium cyanamide, an aldehyde dehydrogenase inhibitor, prior to exposure to toluene, caused a significant decrease and increase, respectively, in toluene-stimulated rates of ROS generation in the CNS and liver. Electron spin resonance spectroscopy, employing the spin trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO), was conducted. Incubation of the spin trap with P2 fractions and toluene or benzaldehyde elicited a spectrum corresponding to the hydroxyl radical. Incubation of benzaldehyde with aldehyde dehydrogenase produced a strong signal that was blocked completely by superoxide dismutase and inhibited partially by catalase, suggesting the presence of superoxide radicals and the involvement of the iron-catalyzed Haber-Weiss reaction leading to the production of hydroxyl radicals. Thus, ROS generation during toluene catabolism may occur at two steps: cytochrome P450 oxidation and aldehyde dehydrogenase oxidation. In addition, GSH may play an important role in protection against the induction of ROS generation in the CNS and liver following exposure to toluene.
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PMID:Free radical induction in the brain and liver by products of toluene catabolism. 839 73

Poisonings with industrial products represent approximately 7% of the cases reported to the poison centres. Ingestion of petroleum distillates induces irritation of the gastrointestinal tract, central nervous system depression and aspiration pneumonitis which may be severe; treatment is mainly supportive. Ethylene and diethylene glycol poisonings produce central nervous system depression, anion gap metabolic acidosis, osmolar gap and acute tubular necrosis; in severe cases, hypocalcaemia, cerebral oedema and heart failure may be observed; treatment often associates supportive measures, haemodialysis and administration of competitive inhibitors of alcohol dehydrogenase (ethanol or 4-methylpyrazole). Glycol ethers induce central nervous system depression and metabolic acidosis; in addition, ethylene glycol monobutyl ether produces haemolysis; monomethyl and monoethyl ethers are responsible for bone marrow and lymphoid organ toxicity, they adversely affect spermatogenesis and are teratogens.
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PMID:[Acute poisoning with industrial products]. 1074 68

Cotreatment of rats with a low hepatotoxic dose (30.7 mg/kg, i.p.) of allyl alcohol (AA) and a higher, but nontoxic, dose (150 mg/kg, oral) of caffeine (CF) potentiated the hepatotoxicity of AA. This was verified by significantly higher levels of plasma alanine aminotransferase (ALT) activity and histopathologically greater severity of lesions in the periportal hepatocytes than those due to AA alone. Treatment of rats with 4-methylpyrazole (4-MP) (0.5 mmol/kg, i.p.) (an inhibitor liver alcohol dehydrogenase) for 30 minutes, followed by similar cotreatment with AA and CF, completely prevented the elevation of plasma levels of ALT and histological damage induced by cotreatment with CF and AA 24 hours following their administration. Severe liver damage induced by cotreatment with CF and AA was further, markedly enhanced by phenobarbital pretreatment (80 mg/kg, i.p., 3 days). Thus, extensive necrosis of periportal hepatocytes was noted, as well as edema and accumulation of inflammatory cells in the necrotic foci caused by such pretreatment. The depression of hepatic nonprotein sulfhydryls resulting from CF plus AA was much more severe than that caused by AA or CF alone and appeared as early as 30 minutes after administration. However, much less marked depletion of protein thiols was observed following similar treatments. Significant increase in lipid peroxidation (as measured by melondialdehyde [MDA] formation) was also observed in rat liver but only 24 hours after administration. The production ofMDA in the rat liver was significantly higher after administration of AA plus CF than after administration of AA alone. Pretreatment of rats with phenobarbital further significantly enhanced the formation of 2,4-dinitrophenylhydrazine (DNP)-reactive metabolite(s) (measured as DNP-acrolein adduct equivalents) in rat liver induced by AA (30.7 mg/kg) plus CF (150 mg/kg) within 1 hour following such treatment. Cotreatment with AA and a higher dose of CF resulted in significantly higher excretion of urinary thioethers or mercapturic acids than in rats treated with AA alone. Thus, these data suggest that an increased bioactivation pathway of acrolein involving a P450 mixed-function oxidase system caused by CF may be involved in such potentiating effects of CF on AA-induced hepatotoxicity in rats.
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PMID:Influence of caffeine on allyl alcohol-induced hepatotoxicity in rats. I. In vivo study. 1139 13

Alcoholic cardiomyopathy is characterized by impaired ventricular function although its toxic mechanism is unclear. This study examined the impact of cardiac overexpression of alcohol dehydrogenase (ADH), which oxidizes ethanol into acetaldehyde (ACA), on ethanol-induced cardiac contractile defect. Mechanical and intracellular Ca(2+) properties were evaluated in ventricular myocytes from ADH transgenic and wild-type (FVB) mice. ACA production was assessed by gas chromatography. ADH myocytes exhibited similar mechanical properties but a higher efficiency to convert ACA compared with FVB myocytes. Acute exposure to ethanol depressed cell shortening and intracellular Ca(2+) in the FVB group with maximal inhibitions of 23.3% and 23.4%, respectively. Strikingly, the ethanol-induced depression on cell shortening and intracellular Ca(2+) was significantly augmented in the ADH group, with maximal inhibitions of 43.7% and 40.6%, respectively. Pretreatment with the ADH inhibitor 4-methylpyrazole (4-MP) or the aldehyde dehydrogenase inhibitor cyanamide prevented or augmented the ethanol-induced inhibition, respectively, in the ADH but not the FVB group. The ADH transgene also substantiated the ethanol-induced inhibition of maximal velocity of shortening/relengthening and unmasked an ethanol-induced prolongation of the duration of shortening/relengthening, which was abolished by 4-MP. These data suggest that elevated cardiac ACA exposure due to enhanced ADH expression may play an important role in the development of alcoholic cardiomyopathy.
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PMID:Overexpression of alcohol dehydrogenase exacerbates ethanol-induced contractile defect in cardiac myocytes. 1189 54

1,4-Butanediol (1,4-BD) is the dihydroxy precursor of gamma-hydroxybutyrate (GHB), a popular recreational drug that has been banned by the United States Food and Drug Administration (FDA) and controlled as a federal schedule I drug. 1,4-BD is enzymatically converted in vivo to GHB by alcohol dehydrogenase (ADH), and overdoses can result in coma, severe respiratory depression, bradycardia, hypothermia, seizures, and death. Presently, there is no antidote. We pretreated CD-1 mice with the ADH antagonist, 4-methylpyrazole (4-MP), to determine if blocking ADH can prevent or decrease toxicity from 1,4-BD overdose. Pretreatment with 4-MP increased the Toxic Dose-50 (TD(50)) of 1,4-BD for the righting reflex from 585 mg/kg (95% CI, 484-707 mg/kg) in control mice to 5,550 mg/kg (95% CI, 5,353-5,756 mg/kg) in pretreated mice. Pretreatment with 4-MP also increased the TD(50) of 1,4-BD for the rotarod test from 163 mg/kg (95% CI, 136-196 mg/kg) in control mice to 4,900 mg/kg (95% CI, 4,812-4,989 mg/kg) in pretreated mice. Pretreatment with 4-MP significantly decreased the toxicity of 1,4-BD in CD-1 mice, presumably by inhibiting its ADH biotransformation to GHB. 4-MP warrants further investigation as a potential antidote for this increasingly abused drug.
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PMID:Pretreatment of CD-1 mice with 4-methylpyrazole blocks toxicity from the gamma-hydroxybutyrate precursor, 1,4-butanediol. 1207 36

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