Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.1.1.1 (alcohol dehydrogenase)
 9,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ethanol oxidation is accomplished primarily by alcohol dehydrogenase. However, a microsomal system involving hydrogen peroxide formation operates at elevated ethanol concentrations. Removal of the resultant hydrogen peroxide may depend on the activity of glutathione peroxidase. In the study, we have examined the effect of chronic ethanol exposure on hepatic glutatione levels and found that ethanol exposure resulted in elevations of hepatic reduced and oxidized glutathione. The dietary inclusion of the sulfhydryl amino acid, D-penicillamine, increased hepatic reduced glutathione (GSH) in both ethanol-dependent and control rats. However, D-penicillamine did not have a differential effect on hepatic GSH when comparing ethanol-dependent and control animals. Following two weeks exposure, the exclusion of ethanol and/or D-penicillamine from the diet for 24 hours resulted in a significant decrease in hepatic GSH.
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PMID:Hepatic glutathione levels in D-penicillamine-fed ethanol-dependent rats. 57 18

Previous metabolic studies in rats have suggested in vivo formation of the acrolein-glutathione (acrolein-GSH) adduct following administration of the highly reactive alpha, beta-unsaturated aldehyde acrolein. Early studies by several investigators demonstrated that similar compounds such as alpha, beta-unsaturated aldehyde-cysteine adducts have toxic (carcinostatic) activity against Ehrlich ascites tumor cells implanted in mice. The current studies investigated the in vivo toxicity associated with the acrolein-GSH adduct in the male Sprague-Dawley rat. The 1:1 acrolein-GSH adduct was synthesized and characterized by physical-chemical methods. Rats given the acrolein-GSH adduct intravenously at 0.5 or 1 mmol/kg developed nephrotoxicity characterized by glucosuria, proteinuria, elevation in serum urea nitrogen, and gross and histologic changes of the kidney. The toxicity was not affected by pretreatment of rats with pyrazole, an alcohol dehydrogenase inhibitor; disulfiram, an inhibitor of aldehyde dehydrogenases; or probenecid, a renal organic anion transport inhibitor. Administration of a similar but nonaldehydic glutathione conjugate, S-n-propylglutathione, did not result in nephrotoxicity in the rat. The nephrotoxicity induced by the acrolein-GSH adduct was inhibited by acivicin, a gamma-glutamyl-transpeptidase inhibitor. These results indicate that the acrolein-GSH adduct requires processing through the first step of the renal mercapturic acid synthesis pathway to be activated to a toxic species.
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PMID:Nephrotoxicity of the 1:1 acrolein-glutathione adduct in the rat. 147 Nov 52

In an attempt to evaluate the effect and interaction of ethanol on endosulfan-induced hepatotoxicity in vivo to adult male rats, both, endosulfan (7.5 mg/kg body wt) and ethanol (1.5 g/kg body wt) were studied separately as well as in combination after a chronic oral exposure of 30 days. When fed separately, both the agents were found to induce microsomal mixed function oxidase (MFO) system in treated animals. A simultaneous induction in the activity of cytosolic GSH-s-transferase was found to be associated with significantly induced ascorbate-induced microsomal lipid peroxidation. Both endosulfan and ethanol showed increasing trends in the activities of reducing equivalent (NADPH)-generating enzymes in liver. The activity of hepatic alcohol dehydrogenase was, however, found to be relatively unaffected. When ethanol was administered in combination with endosulfan, the observed effects on the activities of major drug metabolizing enzymes, microsomal lipid peroxidation and NADPH generation were further pronounced. Findings demonstrated the MFO inducing capability of both endosulfan and ethanol, and showed further that chronic ethanol ingestion might potentiate the in vivo hepatotoxicity of endosulfan if administered in combination.
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PMID:Ethanol potentiates in vivo hepatotoxicity of endosulfan in adult male rats. 181 80

In an attempt to elucidate the mechanism(s) underlying the alcohol-induced pathogenesis of testis, acute as well as chronic studies were undertaken in adult male rats. Ethanol reduced significantly the plasma and testicular testosterone contents in treated rats even at moderate dose levels. The alterations in pituitary gonadotrophins, LH and FSH, demonstrated a central defect in the hypothalamo-hypophyseal-gonadal axis. Major microsomal enzymes involved in the biosynthesis of testosterone, viz. 3 beta-hydroxysteroid dehydrogenase and steroidogenic mixed function oxidases were markedly inhibited in a dose and duration dependent manner. The terminal enzyme 17 beta-hydroxysteroid dehydrogenase was, however, unaffected by ethanol treatments except at a higher dose level of 6 g/kg body wt. Although, the activity of testicular alcohol dehydrogenase was relatively unchanged, a marked induction in the activity of cytosolic conjugation enzyme, GSH-s-transferase was noticed. The present study demonstrates the major role of the metabolism of ethanol in the underlying cause for in vivo toxicity of ethanol and warrants its further consideration.
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PMID:Multiple mechanisms of ethanol-induced gonadal toxicity to adult male rats. 181 81

Human liver class III alcohol dehydrogenase (chi chi-ADH) and glutathione dependent formaldehyde dehydrogenase are the same enzyme. The enzyme, chi chi-ADH, exhibits a kcat of 200 min-1 and a km of 4 microM for the oxidation of formaldehyde, but only in the presence of GSH. In the absence of GSH the enzyme is essentially inactive toward formaldehyde but very active toward long chain alcohols. Thus, as in the rat (Koivusalo, M., Baumann, M., and Uotila, L. (1989) FEBS Letters 257, 105-109), the class III alcohol dehydrogenase and the GSH dependent formaldehyde dehydrogenase are identical enzymes. S-Hydroxymethyl derivatives of 8-thiooctanoate and lipoate are also very active substrates. The activity is specific for class III alcohol dehydrogenase; neither the class I and II nor the horse EE, ES, and SS isozymes oxidize hemithiolacetals. o-Phenanthroline competitively inhibits both activities and the two substrate types compete with each other.
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PMID:Human liver class III alcohol and glutathione dependent formaldehyde dehydrogenase are the same enzyme. 187 53

Three different dehydrogenases able to oxidize formaldehyde were found in the Gram-positive methylotroph, Nocardia sp. 239: an NAD-dependent aldehyde dehydrogenase (NA-ADH), and NAD- and factor-dependent formaldehyde dehydrogenase (FD-FDH), and a dye-linked aldehyde dehydrogenase (DL-ADH). The ratio of the activities observed for the two NAD-linked enzymes varied with growth conditions: batch-wise grown cells had nearly the same activities for both enzymes; in fed batch-wise grown cells (methanol limitation) only FD-FDH was detected. The latter is clearly involved in formaldehyde oxidation, since the enzyme and the factor were found only in methanol-grown cells and the enzyme is specific for formaldehyde. In contrast, the two aldehyde dehydrogenases may have significance for aldehyde dissimilation in general, since both activities could also be demonstrated in ethanol-grown cells (but not in glucose-grown cells) and higher aldehydes are even better substrates than formaldehyde. NA-ADH was purified to homogeneity. The enzyme seems to be a homotetramer since it showed a relative molecular mass of 200,000 and the denaturated form of 55,000. Other characteristics are as follows: the enzyme showed substrate inhibition for the aldehydes tested; optimal activity was found at pH 9.2; the reverse reaction was not observed; the enzyme was specific for NAD; GSH, K+, or NH4+ addition did not stimulate formaldehyde oxidation; the order of NAD and substrate addition to the enzyme was not important; several compounds able to block SH groups were inhibitory. Comparison with NAD-linked aldehyde dehydrogenases from Gram-negative bacteria showed that the Nocardia enzyme is distinct from the enzyme of Pseudomonas putida (EC 1.2.1.46) and of Hyphomicrobium X.
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PMID:Different types of formaldehyde-oxidizing dehydrogenases in Nocardia species 239: purification and characterization of an NAD-dependent aldehyde dehydrogenase. 224 Nov 49

The more recent experimental works on the chemistry, industrial uses and general toxicity (with particular reference to liver cell injury) of allyl alcohol (AA) have been briefly reviewed. AA is inactive per se and its toxic expression is modulated by its alcohol dehydrogenase (ADH) oxidation to form acrolein, which is responsible for the hepatotoxic action. The toxicity of the alcohol (or its metabolite acrolein) is dependent on the concentration of glutathione (GSH). After severe depletion of GSH, the reactive metabolite of AA can bind to essential sulfhydryl groups in the cellular macromolecules, leading to structural and functional modifications which can be responsible for cell death. In this case the appearance of lipid peroxidation could be merely the consequence of the death. GSH synthesis precursors exert a protective role in AA intoxication. The significance of calcium modifications in the course of AA toxicity is still under debate.
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PMID:Aspects of allyl alcohol toxicity. 248

A single intraperitoneal injection of DL-buthionine-S,R-sulfoximine (BSO) (4 mmol/kg) to overnight-starved rats caused a 70% inhibition of hepatic gamma-glutamylcysteine synthetase and induced a decrease in liver-reduced glutathione (GSH) for several hours. There was, however, no difference in hepatic lipid peroxidation, as assessed by malondialdehyde accumulation, between the control and BSO groups. During acute ethanol intoxication (5 g/kg), hepatic lipid peroxidation was increased by approx. 40% within 6 hr. Hepatic [GSH] was also significantly decreased by ethanol. The effect of ethanol on GSH level was not observed in rats pretreated with BSO, though the ethanol-induced enhancement of hepatic lipid peroxidation was potentiated by the BSO pretreatment. Under these conditions there were no apparent effects on blood concentrations of ethanol and acetaldehyde nor on activities of hepatic alcohol dehydrogenase, aldehyde dehydrogenase, glutathione-dependent detoxifying enzymes, superoxide dismutase or catalase. These results suggest that, although a decrease (by BSO) in GSH by itself does not alter the degree of endogenous lipid peroxidation, it is associated with a potentiation of the enhancement of hepatic lipid peroxidation caused by acute ethanol intoxication.
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PMID:Buthionine sulfoximine inhibition of glutathione biosynthesis enhances hepatic lipid peroxidation in rats during acute ethanol intoxication. 257 68

Incubation of isolated hepatocytes with allyl alcohol results in GSH depletion and subsequent cytotoxicity which is prevented by pyrazole, an inhibitor of alcohol dehydrogenase. Both GSH depletion and cytotoxicity were much more rapid when hepatocytes were incubated with acrolein, the reactive metabolite, and were not affected by pyrazole. However, cytotoxicity of both allyl alcohol and acrolein was enhanced by the aldehyde dehydrogenase inhibitors cyanamide and disulfiram. Malondialdehyde, a lipid peroxidation product, was also formed when hepatocytes were incubated with either agent, and treatment of the hepatocytes with a ferric ion chelator, desferrioxamine, or an antioxidant delayed the cytotoxicity without affecting GSH depletion. Although no GSSG was formed and addition of disulfide reductant dithiothreitol did not restore GSH levels, cytotoxicity was prevented if dithiothreitol was added some time after either agent.
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PMID:Allyl alcohol- and acrolein-induced toxicity in isolated rat hepatocytes. 259 53

Hepatotoxicity of allyl formate (AF) was studied in trout, to characterize the response of the teleost liver to a mammalian periportal hepatotoxicant. A dose-dependent decrease in liver nonprotein sulfhydryl (NPSH) concentration was observed at 3, 6, and 24 hr following 9.5, 28, and 95 mg/kg) AF with maximal depression seen at 6 hr (51, 40, and 29% control, respectively). Further evidence for glutathione (GSH) protection against AF toxicity was seen when diethylmaleate, a GSH depleting agent (0.6 ml/kg ip), administered 30 min prior to AF (9.5 and 28 mg/kg), increased AF hepatotoxicity (10-fold shift in the dose-response effect on SGPT). Also, N-acetyl-L-cysteine (150 mg/kg ip), a GSH precursor, protected liver against AF toxicity when injected 5 min prior to and 1, 5, and 9 hr after AF (28 and 95 mg/kg). Pyrazole (375 mg/kg ip), an alcohol dehydrogenase inhibitor, given 4 hr before AF (95 mg/kg), attenuated the histopathological effect of AF. These results indicate that AF, once bioactivated by alcohol dehydrogenase, causes significant toxicity in trout liver. GSH protects against AF-induced effects since greater than 50% decreases in liver GSH are required before toxicity is expressed.
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PMID:Mechanism of allyl formate-induced hepatotoxicity in rainbow trout. 271 94


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