Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1332347 (ADH)
 2,230 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatic cytosol from normal deermice having cytosolic alcohol dehydrogenase (ADH+) also displays retinol dehydrogenase activity and converts retinol to retinoic acid, whereas cytosol from ADH- deermice lacks these enzyme activities and does not produce retinoic acid. Furthermore, microsomes from either strain do not convert retinol to retinoic acid. However, when cytosol from ADH- animals is added to the microsomes, retinoic acid is produced. The obligatory role of retinal as an intermediary step in retinoic acid formation is further shown by isotopic dilution of retinoic acid formed from labeled retinol upon addition of unlabeled retinal. Microsomal retinol dehydrogenase also catalyzes the reduction of retinal to retinol, thereby explaining the decrease in retinoic acid production from retinol in liver cytosol of ADH+ deermice when microsomes are added. Thus, the results of this study indicate that retinal is an obligatory intermediate in the hepatic production of retinoic acid from retinol and that cytosolic and microsomal retinol dehydrogenases play a key role in this process.
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PMID:Retinol forms retinoic acid via retinal. 156 93

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.
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PMID:Age-related effects of chronic ethanol intake on vitamin A status in Fisher 344 rats. 200 3

The elevation of hepatic vitamin A (VA) in zinc deficiency (ZD) is thought to be due, in part, to a reduced synthesis of plasma retinol-binding protein with a subsequent decrease in the release of retinol into the circulation. We hypothesized that the hepatic VA elevation may also be secondary to a change in the activity of enzymes that either regulate retinol degradation or affect the synthesis or hydrolysis of retinyl esters. To examine this question, 20 rats were divided into two groups and pair-fed for 3 wk. ZD rats received a ZD diet (zinc 2.3 mg/kg diet) and controls were fed a zinc-sufficient diet (zinc 50 mg/kg diet). The enzymes studied were retinyl ester hydrolase (REH) and microsomal acyl coenzyme A:retinol acyl transferase (ARAT), the principal enzymes regulating retinyl ester hydrolysis and synthesis. The activities of retinol (alcohol) dehydrogenase (ADH) and retinal oxidase (RO), enzymes regulating retinol degradation to polar metabolites, were also studied. ZD caused an increase in both total hepatic VA concentration and total hepatic VA content, but did not alter the ratio of retinol to retinyl esters. The specific activities of REH and ARAT were not affected by ZD. However, ZD caused a significant reduction in the activity of ADH, the enzyme that catalyzes the first step in retinol oxidation. In contrast, the activity of RO, the enzyme that regulates the irreversible oxidation of retinal to retinoic acid, was significantly increased in ZD rats. These findings indicate that the elevation in hepatic levels of VA in ZD rats may be, in part, secondary to decreased retinol degradation.
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PMID:Effect of zinc deficiency on hepatic enzymes regulating vitamin A status. 340 91

The interaction of ethanol with the oxidative drug-metabolizing enzymes present in liver microsomes results in a number of clinically significant side effects in the alcoholic. Following chronic ethanol consumption, the activity of the microsomal ethanol oxidizing system (MEOS) increases. This enhancement of MEOS activity is primarily due to the induction of a unique microsomal cytochrome P-450 isozyme, which has a high capacity for ethanol oxidation, as shown in reconstituted systems. Normally present in liver microsomes at low levels, this form of cytochrome P-450 increases dramatically after chronic ethanol intake in many species, including baboons. The in-vivo role of cytochrome P-450 in hepatic ethanol oxidation, especially following chronic ethanol consumption, has been conclusively demonstrated in deer-mice lacking liver ADH. Induction of microsomal cytochrome P-450 by ethanol is associated with the enhanced oxidation of other drugs as well, resulting in metabolic tolerance to these agents. There is also increased cytochrome P-450-dependent activation of known hepatotoxins such as carbon tetrachloride and acetaminophen, which may explain the greater susceptibility of alcoholics to the toxicity of industrial solvents and commonplace analgesics. In addition, the ethanol-inducible form of cytochrome P-450 has the highest capacity of all known P-450 isozymes for the activation of dimethylnitrosamine, a potent (and ubiquitous) carcinogen. Moreover, cytochrome P-450-catalyzed oxidation of retinol is accelerated in liver microsomes, which may contribute to the hepatic vitamin A depletion seen in alcoholics. In contrast to chronic ethanol consumption, acute ethanol intake inhibits the metabolism of other drugs via competition for shared microsomal oxidation pathways. Thus, the interplay between ethanol and liver microsomes has a profound impact on the way heavy drinkers respond to drugs, solvents, vitamins, and carcinogens.
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PMID:The microsomal ethanol oxidizing system and its interaction with other drugs, carcinogens, and vitamins. 347 21

The ontogenetic trends in the expression of 25 isozymes in liver, gizzard, heart, and pectoralis muscle of White Leghorn chickens were examined using starch gel electrophoresis. Little change in expression during development was evident in liver S-AAT-A, GPI-A, S-ICDH-A, S-MDH-A and M-MDH-A, in gizzard S-ACON-A, ADH-A, GPI-A, HK-1, HK-3, ME-A PEP-1, and PGM-A, in heart ADH-A, HK-1, HK-3, ME-A, PEP-2, PGM-A, and LDH-A, in pectoralis M-ACON-A, S-ACON-A, ADH-A, HK-1, HK-3, ME-A, PEP-2, and PGM-A, and in liver, gizzard, and heart M-ACON-A, ALD-A, CK-A, G3PDH-A, HK-1, and PGDH-A. Increasing levels of activity were demonstrated in liver ADH-A, ME-A, and PEP-2, in heart M-MDH-A, S-ICDH-A, M-ICDH, and M-AAT-A, and in pectoralis LDH-A, LDH-B, G3PDH-3, ALD-A, CK-A, HK-2, and PGM-B. There was a decrease in the activity of HK-1 in liver and in PEP-1 and PGDH-A in pectoralis muscle throughout development. While CK-C is active in the embryonic pectoralis, CK-A is restricted to later developmental stages. Isozyme expressions in regions of the pectoralis containing fast and slow muscle fibers in 7-month-posthatch individuals were noted and found to be identical. The results underscore the need to use similar developmental stages and tissue samples in comparative electrophoretic studies of birds.
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PMID:A survey of tissue-specific isozyme expressions during chicken ontogeny. 360 63

A full-length 1966-base pair clone of the human class IV alcohol dehydrogenase (sigma-ADH) was isolated from a human stomach cDNA library. The 373-amino acid sigma-ADH encoded by this cDNA was expressed in Escherichia coli. The specific activity of the recombinant enzyme for ethanol oxidation at pH 7.5 and 25 degrees C, calculated from active-site titration of NADH binding, was 92 +/- 9 units/mg. Kinetic analysis of the catalytic efficiency (kcat/KM) of recombinant sigma-ADH for oxidation of primary alcohols indicated broad substrate specificity. Recombinant human sigma-ADH exhibited high catalytic efficiency for oxidation of all-trans-retinol to all-trans-retinal. This pathway is important in the synthesis of the transcriptional regulator all-trans-retinoic acid. Secondary alcohols and 3 beta-hydroxysteroids were inactive with sigma-ADH or were oxidized with very low efficiency. The KM of sigma-ADH for ethanol was 25 mM, and the KM for primary straight chain alcohols decreased substantially as chain length increased. There are important amino acid differences in the alcohol-binding site between the human class IV (sigma) and human class I (beta) alcohol dehydrogenases that appear to explain the high catalytic efficiency for all-trans-retinol, the high kcat for ethanol, and the low catalytic efficiency for secondary alcohols of sigma-ADH relative to beta 1-ADH. For example, modeling the binding of all-trans-retinol in the human beta 1-ADH structure suggested that coordination of retinol to the active-site zinc is hindered by a loop from residues 114 to 120 that is at the entrance to the alcohol-binding site. The deletion of Gly-117 in human sigma-ADH and a substitution of Leu for the bulky Tyr-110 appear to facilitate retinol access to the active-site zinc.
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PMID:Expression and kinetic characterization of recombinant human stomach alcohol dehydrogenase. Active-site amino acid sequence explains substrate specificity compared with liver isozymes. 787 99

The Adh-1 gene product, ADH-A2, the only known murine class I alcohol dehydrogenase, is able to oxidize retinol (vitamin A) into retinaldehyde, the first enzymatic step in the conversion of retinol into its biologically active metabolite retinoic acid. We have investigated the developmental expression pattern of Adh-1 transcripts by in situ hybridization. Transcripts were first detected by embryonic day 10.5 in the mesonephros mesenchyme. During the following gestational days, Adh-1 transcripts were detected in several mesenchymal areas, such as nasal, laterocervical, and genital regions. Adh-1 transcripts were also detected in a small ectodermal domain at the anterior margins of both forelimbs and hindlimbs. During late fetal development. Adh-1 transcripts were found essentially in the epidermis and in a number of tissues which continue to express the gene after birth, such as liver, kidney, gut epithelium, adrenal cortex, testis interstitium, and ovarian stroma. In contrast, a strong expression of Adh-1 was found in the mesenchyme of developing lungs, but not in the adult organ. This highly regulated expression of Adh-1 is discussed with respect to the local synthesis of retinoic acid during development. Although the promoter of the human counterpart of Adh-1 contains a retinoic acid response element (Duester et al. [1991] Mol. Cell. Biol. 11:1638-1646), we report that this element is not conserved in the murine gene. Consistently, Adh-1 promoter-containing reporter constructs were not retinoic acid-inducible in cotransfections assays with RARs and/or RXRs, suggesting that retinoic acid regulation of Adh-1 differs from that of the human gene.
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PMID:Stage and tissue-specific expression of the alcohol dehydrogenase 1 (Adh-1) gene during mouse development. 801 87

Sixty strains of Bacillus sphaericus, including 31 insect pathogens were studied by multilocus enzyme electrophoresis and were classified into 44 zymovars (electrophoretic types). Among the entomopathogenic strains, 11 belong to the same zymovar (Z59) indicating a widespread frequent genotype. Bands of enzyme activity were not detected among the strains for the loci GPI (E.C.5.3.1.9), G6P (E.C.1.1.1.49), 6PG (E.C.1.1.1.44) and ME (E.C.1.1.1.40). The enzymatic loci NP (E.C.2.4.2.1) and ACON (E.C.4.2.1.3) were monomorphic while the other enzymes, MDH (E.C.1.1.1.37), LeDH (E.C.1.4.1.9), ADH (E.C.1.4.1.1), EST (E.C.3.1.1.1), PEP-2 (E.C.3.4.11.1), PEP-3 (E.C.3.4.11) and PEP-D (E.C. 3.4.13.9) were polymorphic. The genetic variation in the non-insect pathogenic group seemed to be greater than in the entomopathogenic group. This latter group appears to be distinct from other strains of these species. All insect pathogens were recovered in the same phenetic cluster and a diagnostic allele is reported for the identification of entomopathogenic strains.
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PMID:Multilocus enzyme electrophoresis on agarose gel as an aid to the identification of entomopathogenic Bacillus sphaericus strains. 820 Aug 59

The requirement of vitamin A (retinol) for successful completion of vertebrate embryogenesis is well established. Retinoid signaling involves a two-step metabolic event in which retinol is first converted to retinal, and then retinal is converted to the active ligand retinoic acid, which modulates the transcriptional activity of a nuclear retinoic acid receptor (RAR). During mouse embryogenesis, retinoic acid is not detected at 6.5 days of embryonic development (E6.5) when gastrulation first initiates, but it is detected at E7.5 and later. This suggests that retinoid signaling during embryogenesis may be initiated during the primitive streak stage. Here we have used whole-mount in situ hybridization to examine E6.5-E8.5 mouse embryos for expression of RAR alpha, RAR beta, RAR gamma, and two enzymes, class IV alcohol dehydrogenase (ADH-IV) and class I aldehyde dehydrogenase (ALDH-I), which have been shown to have retinol and retinal dehydrogenase activities, respectively. At E6.5, RAR alpha mRNA was expressed ubiquitously in embryonic and extraembryonic tissues, RAR gamma mRNA was detected throughout all embryonic tissues, but mRNAs for RAR beta, ADH-IV, and ALDH-I were not detected. By E7.5, RAR alpha mRNA was still ubiquitous, RAR beta mRNA was now observed in presumptive hindbrain ectoderm and adjacent mesenchyme, RAR gamma mRNA was still observed in all embryonic tissues, and ADH-IV as well as ALDH-I mRNAs were now both expressed in primitive streak mesoderm. In E8.5 embryos, RAR alpha mRNA was still ubiquitous, RAR beta mRNA was present in the caudal hindbrain as well as the closed neural tube and foregut, RAR gamma mRNA was widespread but most prevalent in caudal embryonic tissues, and mRNAs for both ADH-IV and ALDH-I were expressed in cranial mesenchyme, somites, and paraxial mesoderm. Thus, ADH-IV and ALDH-1, two metabolic enzymes able to convert retinol to retinoic acid, are both initially expressed in primitive streak mesoderm at E7.5 when retinoic acid is first detectable. On the other hand, RAR alpha and RAR gamma expression is widespread and present at E6.5 prior to retinoic acid detection. These results suggest that upregulation of ADH-IV and ALDH-I gene expression in primitive streak mesoderm may lead to retinoic acid synthesis and initiation of retinoid signaling during mouse embryogenesis.
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PMID:Initiation of retinoid signaling in primitive streak mouse embryos: spatiotemporal expression patterns of receptors and metabolic enzymes for ligand synthesis. 909 25

Kinetic constants of human class IV alcohol dehydrogenase (sigmasigma-ADH) support a role of the enzyme in retinoid metabolism, fatty acid omega-oxidation, and elimination of cytotoxic aldehydes produced by lipid peroxidation. Class IV is the human ADH form most efficient in the reduction of 4-hydroxynonenal (k(cat)/Km: 39,500 mM(-1) min(-1)). Class IV shows high activity with all-trans-retinol and 9-cis-retinol, while 13-cis-retinol is not a substrate but an inhibitor. Both all-trans-retinoic and 13-cis-retinoic acids are potent competitive inhibitors of retinol oxidation (Ki: 3-10 microM) which can be a basis for the regulation of the retinoic acid generation and of the pharmacological actions of the 13-cis-isomer. The inhibition of class IV retinol oxidation by ethanol (Ki: 6-10 mM) may be the origin of toxic and teratogenic effects of ethanol. H2-receptor antagonists are poor inhibitors of human and rat classes I and IV (Ki > 0.3 mM) suggesting a small interference in ethanol metabolism at the pharmacological doses of these common drugs.
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PMID:Retinoids, omega-hydroxyfatty acids and cytotoxic aldehydes as physiological substrates, and H2-receptor antagonists as pharmacological inhibitors, of human class IV alcohol dehydrogenase. 960 Feb 67


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