Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:1.1.1.1 (alcohol dehydrogenase)
9,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytochromes P-450 are extremely important in the oxidative metabolism of a variety of endogenous and exogenous compounds in pro- and eukaryotic organisms. Progress in understanding the structure and mechanism of action of this superfamily of enzymes has been hampered by the properties of the eukaryotic enzymes and the availability of only one well-characterized prokaryotic enzyme as a model. We report here the isolation of a Pseudomonas species which will utilize a monoterpene natural product, alpha-terpineol, as its sole source of carbon and energy. Approximately 1% of the soluble protein in the cell-free extract is a novel cytochrome P-450 (P-450terp). This enzyme and its associated iron sulfur protein electron carrier (terpredoxin) have been purified to homogeneity and their NH2-terminal amino acid sequences determined. The amino acid sequences of six tryptic peptide fragments of cytochrome P-450terp have also been determined. This sequence information was used to clone the gene encoding cytochrome P-450terp. Three clones representing approximately 8 kilobase pairs of unique sequences were selected and sequenced. Five non-overlapping open reading frames (ORFs) were found in the sequences, and the translated sequences were used to search the Protein Identification Resource for comparable proteins. The ORFs were identified as: 1) an alcohol dehydrogenase, 2) an aldehyde dehydrogenase, 3) cytochrome P-450terp, 4) terpredoxin reductase, and 5) terpredoxin. The identification of both the cytochrome P-450terp and terpredoxin DNA sequence was confirmed by the presence of each of the corresponding amino acid sequences found in the purified proteins. The five ORFs were bounded on both the 5' and 3' ends by consensus factor-independent terminator sequences. A consensus promoter sequence was found immediately 5' to the first ORF. These results indicate that we have sequenced the complete terp operon. Comparison of the amino acid sequence of cytochrome P-450terp to that of all other cytochromes P-450 has shown that it is the first member of the gene family CYP108. Preliminary characterization of the chemical and physical properties and the preparation of crystals of this new cytochrome P-450, suitable for x-ray diffraction analysis, indicate that it will be useful in comparison studies with other members of this class of proteins.
...
PMID:Cytochrome P-450terp. Isolation and purification of the protein and cloning and sequencing of its operon. 162 18

There is increasing interest in the possible role of reactive oxygen intermediates in the hepatotoxic actions of alcohol. A variety of mechanisms exist whereby ethanol could increase oxidative stress in the liver. This article briefly reviews two of these possible mechanisms; microsomal generation of reactive oxygen intermediates, and ability of NADH to replace NADPH in promoting microsomal production of oxygen radicals. Microsomes produce superoxide and H2O2, and in the presence of iron, yield potent oxidants which are capable of oxidizing hydroxyl radical scavengers, initiating lipid peroxidation, and causing light emission. These reactions are elevated after chronic ethanol consumption, due in part, to induction of a unique isozyme of cytochrome P-450. Production of NADH as a consequence of ethanol oxidation by alcohol dehydrogenase can affect several metabolic functions. NADH was found to be effective as a reductant for the microsomal electron transfer system, and in catalyzing microsomal generation of reactive oxygen species. Acute ethanol (via production of NADH) and chronic ethanol (induction of P-450IIE1, uncoupling) administration may increase microsomal generation of oxygen radicals; the development of oxidative stress in the liver may contribute to the hepatotoxic actions of alcohol.
...
PMID:Microsomal generation of reactive oxygen species and their possible role in alcohol hepatotoxicity. 166 7

Pyrazole and 4-methylpyrazole (4-MP) are potent, effective inhibitors of alcohol dehydrogenase. Pyrazole and its derivatives also have been shown to affect the cytochrome P-450 dependent monooxygenase system. This study was performed to investigate the effect of 4-MP on the disposition kinetics of antipyrine (AP). Groups of male Fisher 344 rats were given an ip injection of 4-MP (100 mg/kg) or 4-MP HCl (equivalent to 4-MP 100 mg/kg) or an equivalent volume of saline. AP (20 mg/kg) was injected intravenously via the jugular vein catheter 30 minutes later. Blood samples were collected upto 24 hours and assayed by HPLC. 4-MP pretreatment significantly decreased AP clearance from 0.490 +/- 0.032 to 0.095 +/- 0.014 (4-MP HCl) and 0.076 +/- 0.008 (4-MP) L/hr.kg (p less than 0.01). The volume of distribution of AP decreased from 0.82 +/- 0.07 to 0.65 +/- 0.06 (4-MP HCl) and 0.56 +/- 0.04 (4-MP) L/kg (p less than 0.05). Mean residence time increased from 1.68 +/- 0.09 to 6.91 +/- 0.58 (4-MP HCl) and 7.39 +/- 0.56 (4-MP) hr (p less than 0.01). These results demonstrate a significant inhibitory effect of 4-MP on the cytochrome P-450 isozyme(s) which is responsible for AP metabolism in intact animals.
...
PMID:Inhibitory effect of 4-methylpyrazole on antipyrine clearance in rats. 174 Sep 74

Until two decades ago, dietary deficiencies were considered to be the major reason why alcoholics developed liver disease. As the overall nutrition of the population improved, more emphasis was placed on secondary malnutrition. Direct hepatotoxic effects of ethanol were also established, some of which were linked to redox changes produced by reduced nicotinamide adenine dinucleotide (NADH) generated via the alcohol dehydrogenase (ADH) pathway. It was also determined that ethanol can be oxidized by a microsomal ethanol oxidizing system (MEOS) involving cytochrome P-450: the newly discovered ethanol-inducible cytochrome P-450 (P-450IIE1) contributes to ethanol metabolism, tolerance, energy wastage (with associated weight loss), and the selective hepatic perivenular toxicity of various xenobiotics. P-450 induction also explains depletion (and enhanced toxicity) of nutritional factors such as vitamin A. Even at the early fatty-liver stage, alcoholics commonly have a very low hepatic concentration of vitamin A. Ethanol administration in animals was found to depress hepatic levels of vitamin A, even when administered with diets containing large amounts of the vitamin, reflecting, in part, accelerated microsomal degradation through newly discovered microsomal pathways of retinol metabolism, inducible by either ethanol or drug administration. The hepatic depletion of vitamin A was strikingly exacerbated when ethanol and other drugs were given together, mimicking a common clinical occurrence. Hepatic retinoid depletion was found to be associated with lysosomal lesions and decreased detoxification of chemical carcinogens. To alleviate these adverse effects, as well as to correct problems of night blindness and sexual inadequacies, the alcoholic patient should be provided with vitamin A supplementation. Such therapy, however, is complicated by the fact that in excessive amounts vitamin A is hepatotoxic, an effect exacerbated by long-term ethanol consumption. This results in striking morphologic and functional alterations of the mitochondria with leakage of mitochondrial enzymes, hepatic necrosis, and fibrosis. Thus, treatment with vitamin A and other nutritional factors (such as proteins) is beneficial but must take into account a narrowed therapeutic window in alcoholics who have increased needs for such nutrients, but also display an enhanced susceptibility to their adverse effects. Massive doses of choline also exerted some toxic effects and failed to prevent the development of alcoholic cirrhosis. Acetaldehyde (the metabolite produced from ethanol by either ADH or MEOS) impairs hepatic oxygen utilization and forms protein adducts, resulting in antibody production, enzyme inactivation, and decreased DNA repair. It also enhances pyridoxine and perhaps folate degradation and stimulates collagen production by the vitamin A storing cells (lipocytes) and myofibroblasts.(ABSTRACT TRUNCATED AT 400 WORDS)
...
PMID:Alcohol, liver, and nutrition. 177 Jan 92

Until two decades ago, dietary deficiencies were considered to be the only reason for alcoholics to develop liver disease. As the overall nutrition of the population improved, more emphasis was placed on secondary malnutrition and direct hepatotoxic effects of ethanol were established. Ethanol is hepatotoxic through redox changes produced by the NADH generated in its oxidation via the alcohol dehydrogenase pathway, which in turn affects the metabolism of lipids, carbohydrates, proteins, and purines. Ethanol is also oxidized in liver microsomes by an ethanol-inducible cytochrome P-450 (P-450IIE1) that contributes to ethanol metabolism and tolerance, and activates xenobiotics to toxic radicals thereby explaining increased vulnerability of the heavy drinker to industrial solvents, anesthetic agents, commonly prescribed drugs, over-the-counter analgesics, chemical carcinogens, and even nutritional factors such as vitamin A. In addition, ethanol depresses hepatic levels of vitamin A, even when administered with diets containing large amounts of the vitamin, reflecting, in part, accelerated microsomal degradation through newly discovered microsomal pathways of retinol metabolism, inducible by either ethanol or drug administration. The hepatic depletion of vitamin A is strikingly exacerbated when ethanol and other drugs were given together, mimicking a common clinical occurrence. Microsomal induction also results in increased production of acetaldehyde. Acetaldehyde, in turn, causes injury through the formation of protein adducts, resulting in antibody production, enzyme inactivation, decreased DNA repair, and alterations in microtubules, plasma membranes and mitochondria with a striking impairment of oxygen utilization. Acetaldehyde also causes glutathione depletion and lipid peroxidation, and stimulates hepatic collagen production by the vitamin A storing cells (lipocytes) and myofibroblasts.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Hepatic, metabolic and toxic effects of ethanol: 1991 update. 192 31

The in vitro metabolism of [14C]toluene by liver microsomes and liver slices from male Fischer F344 rats and human subjects has been compared. Rat liver microsomes produced only benzyl alcohol from toluene. Liver microsomes from human subjects metabolized toluene to benzyl alcohol, benzaldehyde, and benzoic acid. Liver microsomes from one human donor also produced p-cresol and o-cresol. The overall rate of toluene metabolism by human liver microsomes was 9-fold greater than by rat liver microsomes. Human liver microsomal metabolism of benzyl alcohol to benzaldehyde required NADPH and was inhibited by carbon monoxide and high pH (pH 10). but was not inhibited by ADP-ribose or sodium azide. These results suggest that cytochrome P-450, rather than alcohol dehydrogenase, was responsible for the metabolism of benzyl alcohol to benzaldehyde. Human and rat liver slices metabolized toluene to hippuric acid and benzoic acid. The overall rate of toluene metabolism by human liver slices was 1.3-fold greater than by rat liver slices. Cresols and cresol conjugates were not detected in human or rat liver slice incubations. Covalent binding of [14C]toluene to human liver microsomes and slices was 21-fold and 4-fold greater than to the comparable rat liver preparations. Covalent binding did not occur in the absence of NADPH, was significantly decreased by coincubation with cysteine, glutathione, or superoxide dismutase, and was unaffected by coincubation with lysine. Protease and ribonuclease digestion decreased the amount of toluene covalently bound to human liver microsomes by 78% and 27% respectively. Acid washing of human liver microsomes had no effect on covalent binding.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Metabolism and covalent binding of [14C]toluene by human and rat liver microsomal fractions and liver slices. 198 39

The present study was designed to investigate the interaction of age and ethanol on vitamin A status in rats. Rats aged 2 and 19 mo were fed a liquid diet containing 36% of total energy as ethanol or pair-fed a diet containing isoenergetic carbohydrate in place of ethanol. After 3 wk older rats had lower serum retinol (P = 0.04) and higher vitamin A concentrations in liver (P = 0.0001), esophagus (P = 0.0001) and the proximal (P = 0.03) and distal (P = 0.0001) colon than younger animals. Hepatic microsomal cytochrome P-450, retinyl ester hydrolase (REH) and cellular retinol-binding protein (cRBP) were significantly reduced; acyl coenzyme A: retinol acyltransferase (ARAT) was increased; and alcohol (retinol) dehydrogenase (ADH) activity was unchanged with age. Ethanol ingestion increased serum retinol as well as esophageal and colonic vitamin A levels in both age groups. Hepatic cRBP decreased further in the older rats with ethanol feeding, but no change was noted in the percentage of hepatic vitamin A as retinol or retinyl esters. Ethanol ingestion decreased REH (P = 0.0001) and ARAT activities (P = 0.02) and increased cytochrome P-450 (P = 0.04) but had no effect on the activity of ADH in either age group. These data indicate that, regardless of age, chronic ethanol ingestion significantly alters the tissue distribution of vitamin A; however, ethanol reduced cRBP levels only in older rats.
...
PMID:Age-related effects of chronic ethanol intake on vitamin A status in Fisher 344 rats. 200 3

We investigated the effects of ethylene glycol (EG) on the hepatic drug metabolizing enzymes. The exposed group was given 1% EG solution and the control group was provided with distilled water for 2 weeks ad libitum. The body weight of the exposed group was the same as that of the control group. The liver and kidney weight per body weight did not change. The daily drinking volume for the exposed group on the average showed an increase of 13.5% over that of the control group. Hematologically and biochemically, anemia, liver and renal dysfunction were not seen. The content of the hepatic microsomal cytochrome P-450 in the exposed group showed an increase of 17% over that of the control group, but the contents of cytochrome b5, protoheme and the activities of NADPH-cytochrome c reductase, NADH-ferricyanide reductase did not change. The activities of the hepatic cytosolic alcohol dehydrogenase and glutathione reductase, glutathione peroxidase, glutathione-S-transferase also did not change. These results indicate that the hepatic microsomal cytochrome P-450 takes part in the metabolism of EG.
...
PMID:[Effects of ethylene glycol on drug metabolizing enzymes in rat liver]. 202 9

1. Age-related changes in hepatic hydroxylation of azoxymethane (AZO) to methylazoxymethanol (MAM), as well as colonic phase I metabolism of MAM by alcohol dehydrogenase (ADH) were examined in young (2-4 months), middle-aged (12-14 months), and old (22-24 months) male Fischer 344 rats. In addition, the possibility that colonic glucuronyltransferase might be involved in the biotransformation of MAM was also investigated. 2. A significant decrease in hepatic conversion of AZO to MAM was found in old vs young rats, concomitant with a decrease in hepatic cytochrome P-450 content, while no age-related difference was found in the colonic metabolism of MAM by ADH. MAM inhibition of colonic 4-methylumbelliferone glucuronyltransferase was non-competitive, suggesting indirectly that colonic glucuronyltransferase is not involved in conjugation of MAM. 3. It is concluded that ageing in the male Fischer 344 rat results in alternations of AZO and MAM biotransformation which indicate that AZO may be less carcinogenic in older rats.
...
PMID:Age-related changes in biotransformation of azoxymethane and methylazoxymethanol in vitro. 211 89

Ethanol is hepatotoxic through redox changes produced by the NADH generated in its oxidation via the alcohol dehydrogenase pathway, which in turn affects the metabolism of lipids, carbohydrates, proteins and purines. Ethanol is also oxidized in liver microsomes by an ethanol-inducible cytochrome P-450 (P-450IIE1) which contributes to ethanol metabolism and tolerance, and activates xenobiotics to toxic radicals thereby explaining increased vulnerability of the heavy drinker to industrial solvents, anesthetic agents, commonly prescribed drugs, over-the-counter analgesics, chemical carcinogens and even nutritional factors such as vitamin A. Induction also results in energy wastage and increased production of acetaldehyde. Acetaldehyde, in turn, causes injury through the formation of protein adducts, resulting in antibody production, enzyme inactivation, decreased DNA repair, and alterations in microtubules, plasma membranes and mitochondria with a striking impairment of oxygen utilization. Acetaldehyde also causes glutathione depletion and lipid peroxidation, and stimulates hepatic collagen synthesis, thereby promoting fibrosis.
...
PMID:Mechanism of ethanol induced hepatic injury. 218 86


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---