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

To assess the importance of non-ADH ethanol metabolism, ADH-negative and ADH-positive deermice were fed liquid diets containing ethanol or isocaloric carbohydrate for 2-4 weeks. Blood ethanol disappearance rate increased significantly after chronic ethanol feeding in both strains. Although at low ethanol concentrations (between 5 and 10 mM) there was no significant difference between ethanol-fed and pair-fed control animals, at high ethanol concentrations (between 40 and 70 mM) blood ethanol elimination rates were increased significantly after chronic ethanol feeding in both ADH-positive and ADH-negative animals. There was no significant effect of the catalase inhibitor 3-amino-1,2,4-triazole on the ethanol elimination/rates in both strains. Whereas catalase and ADH activities were not altered after chronic ethanol treatment, the activity of the microsomal ethanol-oxidizing system (MEOS) was enhanced three to four times in both strains, and microsomal cytochrome P-450 content was also increased significantly. When MEOS activity was expressed per cytochrome P-450 content, it was higher in ADH-negative than in ADH-positive animals, and it increased after ethanol administration. When microsomal proteins were separated by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis, ethanol-fed animals had a distinct band which reflected the increase in microsomal cytochrome P-450 content and seemed to reflect a unique form of cytochrome P-450 induced by ethanol. Thus, despite the absence of the ADH pathway, a large amount of ethanol was metabolized by MEOS in ADH-negative deermice; this was associated with increased blood ethanol elimination rates, enhanced MEOS activity, and quantitative and qualitative changes of cytochrome P-450.
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PMID:Ethanol metabolism in vivo by the microsomal ethanol-oxidizing system in deermice lacking alcohol dehydrogenase (ADH). 637 Feb 62

Several studies in our unit showed that in men, baboons, rats and deermice, blood ethanol clearance is significantly accelerated at ethanol concentrations higher than the levels needed to effectively saturate the low Km forms of ADH present in animals, thereby incriminating a high Km non-ADH system such as microsomal ethanol oxidizing system (MEOS). Furthermore, kinetics of blood ethanol clearance were consistent with the Km of MEOS. After chronic ethanol consumption, there was an increase in rates of ethanol elimination and in the activity of MEOS. There was an associated rise in microsomal cytochrome P-450, including a form (different from that of a non-ADH pathway of ethanol metabolism and its increase after chronic ethanol consumption was most conclusively shown in ADH-negative deermice. Microsomal induction was also associated with enhanced metabolism of other drugs, resulting in metabolic drug tolerance. In addition, there was increased activation of known hepatotoxic agents (such as CCl4 and acetaminophen) which may explain the enhanced susceptibility of alcoholics to the toxicity of solvents and commonly used drugs. There was enhanced activation of procarcinogens, sometimes at concentrations much lower than those required for other microsomal inducers. Moreover, catabolism of retinoic acid was accelerated possibly contributing to hepatic vitamin A depletion. In conclusion, after chronic ethanol consumption, enhanced MEOS activity and concomitant cytochrome P-450 changes may contribute to accelerated ethanol and drug metabolism and associated activation of hepatotoxic agents and carcinogens.
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PMID:Microsomal ethanol oxidizing system (MEOS): interaction with ethanol, drugs and carcinogens. 641 69

The activities of several hepatic microsomal, mitochondrial, and cytosolic drug-metabolizing enzymes, as well as the components of the cytochrome P-450 system, were determined in vitro for control, sham-operated, and uremic rats. Chronic renal failure (CRF) was produced by a two-stage surgical procedure. In this model, the animals were maintained for 21 days postoperatively before assay. During this time, serum urea nitrogen (SUN) levels rose from control levels of 21 mg/dl to an average of 63 mg/dl. Enzymes assayed included microsomal N-, O-, and S-demethylases, esterase, and UDP-glucuronyl transferase; monoamine oxidase; and alcohol dehydrogenase. CRF caused decreases of 24-32% in N- and O-demethylase activities, while S-demethylase, esterase, UDP-glucuronyl transferase, and monoamine oxidase activities were not altered significantly. Alcohol dehydrogenase activity was increased 71%. In addition, the functional components of the microsomal mixed-function oxidase system were assayed. CRF caused a 26% decrease in cytochrome P-450 levels, as compared to sham-operated controls, but cytochrome b5 and NADPH-cytochrome c (P-450) reductase were not altered. CRF caused an increase in hexobarbital sleeping time of more than 7-fold. In each case, alterations in enzyme activities or cytochrome P-450 correlated with the extent of renal failure, as determined by elevated SUN levels.
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PMID:Hepatic drug metabolism in rats with experimental chronic renal failure. 642 78

In an attempt to better understand the mechanism of the fetal damage caused by ethanol, we studied the effects of its administration on the activity of some ethanol metabolizing enzymes in mice fetuses. Animals were given a single ethanol injection (0.01 ml of a 25% solution in 0.9% sodium chloride per gram of body weight) on day 12 of pregnancy and were divided into groups that were killed 24, 48, and 72 hours later. The fetal and maternal livers were isolated, homogenized, and divided into subcellular fractions. Alcohol dehydrogenase, NADH-cytochrome C reductase, NADPH-cytochrome C reductase, and cytochrome P-450 activities were measured and compared with those of control animals injected with saline solution. We found that ethanol caused (1) a significant but transient increase in fetal alcohol dehydrogenase activity, (2) a significant and persistent increase in fetal cytochrome P-450 and NADPH-cytochrome C reductase activities, and (3) no change in fetal NADH-cytochrome C reductase activity. These effects were similar although quantitatively smaller than those observed in the maternal liver and disappeared after pretreatment with metyrapone. This work demonstrates that ethanol has a similar effect upon both maternal and fetal ethanol metabolizing enzymes and gives experimental support to the possibility that a reactive product of the interaction between ethanol and the cytochrome P-450 system may be responsible for the embryotoxic effects of this compound.
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PMID:Effects of ethanol on alcohol dehydrogenase and microsomal ethanol oxidative system activities in fetal mice. 643 26

Microsomes isolated from rats treated for 3 days with 200 mg/kg body wt. per day of pyrazole, a potent inhibitor of alcohol dehydrogenase, catalyzed the oxidation of ethanol and 2-butanol at rates 2-3-fold higher than saline controls. This increase was blocked by carbon monoxide, and was not associated with an increase in the oxidation of aminopyrine or in the content of cytochrome P-450, suggesting the possibility of an induction of an alcohol-preferring cytochrome P-450 by pyrazole. Microsomes from the pyrazole-treated rats displayed a stereochemical preference for the oxidation of the (+)-2-butanol isomer over the (-)-2-butanol isomer, which was blocked by carbon monoxide, and also displayed a type-2 binding spectrum with dimethylsulfoxide or 2-butanol. No such spectrum was found with the saline controls. These properties are similar to those which are observed with microsomes from chronic ethanol-fed rats. These similarities suggest the possibility that pyrazole treatment may induce a cytochrome P-450 isozyme with properties similar to the ethanol-inducible cytochrome P-450.
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PMID:Increased microsomal oxidation of alcohols after pyrazole treatment and its similarities to the induction by ethanol consumption. 646 9

The relationship between the serum concentration ratio of 5,5-dimethyl-2,4-oxazolidinedione (DMO) to trimethadione (TMO) and the cytochrome P-450-dependent drug-oxidizing enzyme activity in rats pretreated with different dose levels of bromobenzene (BZ) and allyl alcohol (AA) was investigated. Pretreatment of rats with increasing dose levels of BZ and AA resulted in a prolongation of TMO half-life, an increase in the area under the curve (AUC), a decrease in clearance (Cl) and a decrease in the apparent volume of distribution (Vd). At each dose of BZ and AA used, there was a good correlation between DMO/TMO ratios in serum and activities of hepatic cytochrome P-450-dependent drug-oxidizing enzymes, such as cytochrome P-450 content, aminopyrine N-demethylase, TMO N-demethylase and aniline hydroxylase activities. However, the correlation between the serum DMO/TMO ratio and the alcohol dehydrogenase activity in AA treated rats was poor, whereas the activity of this enzyme was not changed in BZ treated rats. These results, together with the previous findings, indicate that determination of the serum levels of TMO and DMO may a useful index of drug-oxidizing capacity of rats with hepatic necrosis specified regions.
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PMID:Effects of allyl alcohol and bromobenzene on trimethadione metabolism in the rat. 647 97

Liver microsomes from rabbits treated chronically with ethanol were solubilized and fractionated to yield a new isozyme of cytochrome P-450 in a homogeneous state. This cytochrome, designated as isozyme 3a on the basis of its relative electrophoretic mobility, is distinct from the known terminal amino acid sequences. In addition, peptide mapping by high performance liquid chromatography following trypsinolysis indicates that form 3a is a unique gene product. This cytochrome has unusually high activity in the oxidation of ethanol and other alcohols to aldehydes and in the rho-hydroxylation of aniline as compared with the other isozymes of P-450. The ethanol-oxidizing activity of isozyme 3a, which requires the presence of NADPH and NADPH-cytochrome P-450 reductase and is stimulated by the presence of phosphatidylcholine, is not due to contamination by catalase or an NAD+-or NADP+-dependent alcohol dehydrogenase.
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PMID:Alcohol oxidation by isozyme 3a of liver microsomal cytochrome P-450. 668 96

Previous work has shown that induction of a high-affinity NADPH-dependent nitrosodimethylamine demethylase (NDMAd) in liver microsomes occurs in rats due to fasting, ethanol consumption, and streptozotocin-induced diabetes. Several lines of observations suggest that this is due to the induction of specific cytochrome P-450 isozymes. Induction of P-450 species by ethanol has also been observed by other investigators. Since each of the above altered metabolic states has in common elevated levels of ketone bodies, the possible role of acetone, a known inducer of NDMAd, in the induction of the demethylase activity was investigated. Levels of endogenous acetone in fasted rats correlated (r = 0.72) with a three- to fourfold increase in NDMAd activity. However, a dose-response experiment showed endogenous levels of acetone to be capable of causing at most 40% of the induction in fasted rats. This suggests that other ketone bodies or factors may have contributed to the induction. The induction of NDMAd by ethanol was enhanced by alcohol dehydrogenase inhibitors pyrazole and acetaldehyde oxime, suggesting that ethanol, rather than its metabolites, was responsible for the induction.
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PMID:Studies on the mechanisms of induction of N-nitrosodimethylamine demethylase by fasting, acetone, and ethanol. 670 8

The volatile hydrocarbons ethane and n-pentane are produced at increased rates by isolated perfused rat liver during the metabolism of acutely ethanol. The effect is half-maximal at 0.5 mM-ethanol, and its is not observed when inhibitors of alcohol dehydrogenase such as 4-methyl- or 4-propyl-pyrazole are also present. Propanol, another substrate for the dehydrogenase, is also active. Increased alkane production can be initiated by adding acetaldehyde in the presence of 4-methyl- or 4-propyl-pyrazole. An antioxidant, cyanidanol, suppresses the ethanol-induced alkane production. The data obtained with the isolated organ demonstrate that products known to arise from the peroxidation of polyunsaturated fatty acids are formed in the presence of ethanol and that the activity of alcohol dehydrogenase is required for the generation of the active radical species. The mere presence of ethanol, e.g. at binding sites of special form(s) of cytochrome P-450, it not sufficient to elicit an increased production of volatile hydrocarbons by rat liver.
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PMID:Role of alcohol dehydrogenase activity and the acetaldehyde in ethanol- induced ethane and pentane production by isolated perfused rat liver. 675 24

Di(2-ethylhexyl) phthalate (DEHP), a commonly used plasticizer and microchemical environmental pollutant, produces subtle changes in hepatic function as judged by increase in liver weight and morphological and biochemical alterations. It can modify the biological response of drugs and other xenobiotics. Such interactions appear to occur at the pharmacokinetic phase, as DEHP was found to alter the activity of microsomal drug-metabolizing enzymes and ethanol metabolism. DEHP produced a time- and route-dependent effect on the hepatic cytochrome P-450 contents and activity of aminopyrine N-demethylase, aniline hydroxylase, alcohol dehydrogenase and high and low Km aldehyde dehydrogenases when given orally or intraperitoneally. Under in vitro conditions, DEHP produced no effect on the activity of aminopyrine N-demethylase or aniline hydroxylase, while mono(2-ethylhexyl) phthalate (MEHP) and 2-ethylhexanol (2-EH) significantly inhibited their activity at concentrations ranging from 2.5 to 15.0 mM. Activity of aminopyrine N-demethylase and aniline hydroxylase was also inhibited by dimethyl phthalate (DMP) and dibutyl phthalate (DBP) after a single oral administration. In view of the possibility of the human exposure to phthalates and other xenobiotics simultaneously, these observations are of great significance.
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PMID:Hepatic effects of phthalate esters. 675 61


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