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)

A comparative study is made of the stereospecificity of two particulate retinol dehydrogenases from bovine eyes and of horse liver alcohol dehydrogenase. The particulate retinol dehydrogenase of outer segments reacts with the all-trans isomers of retinaldehyde and retinol but not with the 11-cis compounds. In contrast, a particulate retinol dehydrogenase present in pigment epithelium reacts preferentially with the 11-cis compounds. Horse liver alcohol dehydrogenase (EC 1.1.1.1.) can convert both isomers, but the all-trans isomers are clearly preferred. Differences with regard to cofactor preference and stability are also noted. The outer segment enzyme clearly functions in the rhodopsin cycle. It is unlikely that the 11-cis retinol dehydrogenase from pigment epithelium is directly involved in providing 11-cis retinaldehyde from rhodopsin regeneration, but it may serve to make available 11-cis retinaldehyde from rhodopdsin, digested in phagocytized rod sacs, for the synthesis of visual pigment by the visual cells.
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PMID:Biochemical aspects of the visual process. XXVII. Stereospecificity of ocular retinol dehydrogenases and the visual cycle. 112 52

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

Ethanol acts as a teratogen causing brain, craniofacial, and limb abnormalities in those suffering from fetal alcohol syndrome. Normal embryonic development of the vertebrate nervous system and limbs has recently been shown to be governed by retinoic acid, the active form of vitamin A. Retinol dehydrogenase is an enzyme needed to convert vitamin A (retinol) to retinoic acid, a molecule that specifies embryonic pattern formation by controlling gene expression. Ethanol acts as a competitive inhibitor of the retinol dehydrogenase activity attributed to mammalian alcohol dehydrogenase (ADH), an enzyme that uses both retinol and ethanol as substrates. An hypothesis is presented in which many of the abnormalities observed in fetal alcohol syndrome may be caused by high levels of ethanol acting as a competitive inhibitor of ADH-catalyzed retinol oxidation in the embryo or fetus. This would presumably result in a reduction of retinoic acid synthesis in embryonic tissues such as the nervous system and limbs that require critical levels of this molecule to specify spatial patterns.
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PMID:A hypothetical mechanism for fetal alcohol syndrome involving ethanol inhibition of retinoic acid synthesis at the alcohol dehydrogenase step. 187 46

Retinoic acid regulation of one member of the human class I alcohol dehydrogenase (ADH) gene family was demonstrated, suggesting that the retinol dehydrogenase function of ADH may play a regulatory role in the biosynthetic pathway for retinoic acid. Promoter activity of human ADH3, but not ADH1 or ADH2, was shown to be activated by retinoic acid in transient transfection assays of Hep3B human hepatoma cells. Deletion mapping experiments identified a region in the ADH3 promoter located between -328 and -272 bp which confers retinoic acid activation. This region was also demonstrated to confer retinoic acid responsiveness on the ADH1 and ADH2 genes in heterologous promoter fusions. Within a 34-bp stretch, the ADH3 retinoic acid response element (RARE) contains two TGACC motifs and one TGAAC motif, both of which exist in RAREs controlling other genes. A block mutation of the TGACC sequence located at -289 to -285 bp eliminated the retinoic acid response. As assayed by gel shift DNA binding studies, the RARE region (-328 to -272 bp) of ADH3 bound the human retinoic acid receptor beta (RAR beta) and was competed for by DNA containing a RARE present in the gene encoding RAR beta. Since ADH catalyzes the conversion of retinol to retinal, which can be further converted to retinoic acid by aldehyde dehydrogenase, these results suggest that retinoic acid activation of ADH3 constitutes a positive feedback loop regulating retinoic acid synthesis.
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PMID:Retinoic acid response element in the human alcohol dehydrogenase gene ADH3: implications for regulation of retinoic acid synthesis. 199 13

The relationship between excess vitamin A intake and accumulation in various tissues, including the liver, was studied in rats fed for 45 d four levels of vitamin A: 1, 6, 30 and 100 IU/kcal. As vitamin A intake increased, progressively smaller fractions of the administered vitamin A were recovered in tissue. The decrease in fractional recovery in the tissues examined was calculated from the differences between intake, tissue level and excretion, and was found to increase after administration of high vitamin A diets. This could be explained, at least in part, on the basis of an enhanced rate of vitamin A degradation as a function of the increased concentration of retinol in the liver. At high tissue retinol concentrations, calculated rates of retinol metabolism via the hepatic cytosolic retinol dehydrogenase (EC 1.1.1.1) and the recently discovered microsomal retinol dehydrogenase and oxidase vastly exceeded the decrease in fractional recovery of vitamin A accumulation in the tissues. This calculated rise in metabolic rate was verified by a corresponding increase in urinary polar metabolites derived from labeled retinol. Thus, accelerated catabolism as a function of increased hepatic vitamin A concentration may provide a homeostatic mechanism which offsets in part excessive vitamin A accumulation.
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PMID:Role of vitamin A degradation in the control of hepatic levels in the rat. 266 5

A protein from rat testes that catalyzes the oxidation of ethanol in the presence of NAD+, but not NADP+, has been characterized enzymatically and compared to that of hepatic alcohol dehydrogenase obtained from the same animals. The testicular enzyme, like the hepatic enzyme, has a Km value for ethanol in the 0.5-1.0-mM range and can utilize other alcohols such as n-propanol, n-butanol, and isobutanol, although the Km values for these other alcohols are considerably lower (0.03-0.08 mM) that that for ethanol. The testicular enzyme is more heat-labile than is the hepatic enzyme. Finally, the testicular enzyme catalyzes the oxidation of retinol and its retinol dehydrogenase activity is inhibited by ethanol.
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PMID:Characterization of rat testicular alcohol dehydrogenase. 293 16

Specific assays, based on gas chromatography-mass spectrometry and high-performance liquid chromatography, were used to quantify the conversion of retinol and retinal into retinoic acid by the pig kidney cell line LLC-PK1. Retinoic acid synthesis was linear for 2-4 h as well as with graded amounts of either substrate to at least 50 microM. Retinoic acid concentrations increased through 6-8 h, but decreased thereafter because of substrate depletion (t1/2 of retinol = 13 h) and product metabolism (1/2 = 2.3 h). Retinoic acid metabolism was accelerated by treating cells with 100 nM retinoic acid for 10 h (t1/2 = 1.7 h) and was inhibited by the antimycotic imidazole ketoconazole. Feedback inhibition was not indicated since retinoic acid up to 100 nM did not inhibit its own synthesis. Retinol dehydrogenation was rate-limiting. The reduction and dehydrogenation of retinal were 4-8-fold and 30-60-fold faster, respectively. Greater than 95% of retinol was converted into metabolites other than retinoic acid, whereas the major metabolite of retinal was retinoic acid. The synthetic retinoid 13-cis-N-ethylretinamide inhibited retinoic acid synthesis, but 4-hydroxylphenylretinamide did not. 4'-(9-Acridinylamino)methanesulfon-m-anisidide, an inhibitor of aldehyde oxidase, and ethanol did not inhibit retinoic acid synthesis. 4-Methylpyrazole was a weak inhibitor: disulfiram was a potent inhibitor. These data indicate that retinol dehydrogenase is a sulfhydryl group-dependent enzyme, distinct from ethanol dehydrogenase. Homogenates of LLC-PK1 cells converted retinol into retinoic acid and retinyl palmitate and hydrolyzed retinyl palmitate. This report suggests that substrate availability, relative to enzyme activity/amount, is a primary determinant of the rate of retinoic acid synthesis, identifies inhibitors of retinoic acid synthesis, and places retinoic acid synthesis into perspective with several other known pathways of retinoid metabolism.
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PMID:Retinol metabolism in LLC-PK1 Cells. Characterization of retinoic acid synthesis by an established mammalian cell line. 375 84

Alcohol dehydrogenase (ADH; EC 1.1.1.1) activity in Xenopus laevis was highest in liver tissue, with decreasing activities in kidney, heart, and gut tissues, respectively. Essentially no activity was found among other tissues screened, including lung, ovary, eye, and testes. Also, there was no apparent sexual dimorphism of ADH activity in either liver or kidney tissue. All ADH isozymes were inhibited by 10 mM pyrazole, and no eye-specific retinol dehydrogenase activity was detected on starch gel electropherograms. Isozyme patterns from 418 offspring from 11 different crosses could be explained genetically assuming the presence of two structural genes coding for ADH production: one carrying two electrophoretically separable variants and the other showing quantitative variation in its expression. The ADH system in X. laevis should be useful for studies concerning the molecular mechanisms governing the expression of ADH activity in vertebrate development.
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PMID:Alcohol dehydrogenase isozymes in the clawed frog, Xenopus laevis. 636 54

The effect of chronic alcohol consumption on vitamin A metabolism was investigated in male rats. Liquid diets containing five times the NRC requirement for vitamin A and varied levels of ethanol were fed. The vitamin A content of the liver was decreased in rats receiving alcohol. Liver lipids were only slightly elevated in alcohol-fed rats. Hepatic vitamin A storage was also decreased in rats fed 30% calories as alcohol and beta-carotene or vitamin A at the NRC requirement level, but not in rats fed one-sixth the NRC requirement as vitamin A. The activities of alcohol dehydrogenase, NADPH cytochrome c reductase, and retinol dehydrogenase were not altered in hepatic or testicular tissue by the vitamin A or alcohol content of the diet. When an intragastric dose of [3H]retinyl acetate or [14C]beta-carotene was administered, fecal excretion of radioactivity was lower than controls in rats receiving 30% ethanol in the diet for a total of 4 weeks, for 1 week following 7 weeks of control diet consumption, and after an acute dose of ethanol. Recovery of the 3H label was greater in the testes of rats chronically consuming ethanol. When a solution containing [3H]retinyl acetate or [3H]beta-carotene with or without ethanol was injected into intestinal segments, no alterations in absorption of retinyl acetate or beta-carotene due to ethanol occurred. It is concluded that alcohol consumption results in decreased hepatic vitamin A storage, which is not due to the malabsorption of either retinyl acetate or beta-carotene, or to altered activities of several enzymes involved in ethanol and vitamin A metabolism.
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PMID:Effect of chronic alcohol consumption and moderate fat diet on vitamin A status in rats fed either vitamin a or beta-carotene. 668 29

A general summary of typical results involving animal studies is shown in TABLE 7. A consistent and established finding is a reduction of plasma vitamin A concentration in zinc-deficient animals despite diets adequate in vitamin A. However, it appears that the depressed plasma vitamin A is not a result of zinc deficiency per se but rather is nonspecific, resulting from food- and growth-restriction factors associated with zinc deficiency. Food restriction apparently is the critical factor, since both immature and mature nongrowing zinc-deficient animals have exhibited the decreased plasma vitamin A concentration. However, this point needs clarification. Liver vitamin A concentration is usually unaltered by the zinc deficiency, suggesting no defect in absorption or transport to the liver. In regard to retinol-binding protein, it appears from the animal studies that zinc deficiency per se has an effect on both the plasma and liver RBP concentrations. We have hypothesized that zinc deficiency impairs RBP synthesis. It is speculated that only severe zinc deficiency results in a deficit of a sufficient magnitude for impairment of vitamin A metabolism at the cellular level. For example, retinene reductase, an apparent zinc-metallo alcohol dehydrogenase of the retina, appears to be sensitive to a severe zinc deficiency in animal studies. In humans, impaired dark adaptation may be a result of inadequate supplies of the metabolizable zinc necessary to maintain the activity of the enzyme system. Thus, the conversion (dehydrogenation) of vitamin A alcohol to vitamin A aldehyde is impaired, with a resulting abnormality in dark adaptation, i.e., night blindness. Indeed, the limited number of human studies suggest that zinc supplementation may be beneficial to vitamin A metabolism only in conditions where zinc deficiency is prevalent as indicated by low (less than 70 micrograms/100 ml) plasma zinc. Conversely, zinc supplementation is of little benefit in conditions where vitamin A metabolism is altered but zinc status is normal. Therefore, definitive clinical studies involving primary zinc deficiency must be conducted before final conclusions can be made regarding the interrelationships of zinc and vitamin A in health and disease.
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PMID:The vitamin A-zinc connection: a review. 678 55


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