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)

Enzymes encoded by two gene families, alcohol dehydrogenase ( ADH) and aldehyde dehydrogenase ( ALDH), mediate alcohol metabolism in humans. Allelic variants have been identified that alter metabolic rates and influence risk for alcoholism. Specifically, ADH1B*47His (previously ADH2-2) and ALDH2-2 have been shown to confer protection against alcoholism, presumably through accumulation of acetaldehyde in the blood and a resultant 'flushing response' to alcohol consumption. In the current study, variants at ADH1B (previously ADH2), ADH1C (previously ADH3), and ALDH2 were assayed in DNA extracts from participants belonging to a Southwest American Indian tribe ( n=490) with a high prevalence of alcoholism. Each subject underwent a clinical interview for diagnosis of alcohol dependence, as well as evaluation of intermediate phenotypes such as binge drinking and flushing response to alcohol consumption. Detailed haplotypes were constructed and tested against alcohol dependence and related intermediate phenotypes using both association and linkage analysis. ADH and ALDH variants were also assayed in three Asian and one African population (no clinical data) in order to provide an evolutionary context for the haplotype data. Both linkage and association analysis identified several ADH1C alleles and a neighboring microsatellite marker that affected risk of alcohol dependence and were also related to binge drinking. These data strengthen the support for ADH as a candidate locus for alcohol dependence and suggest further productive study.
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PMID:Allelic variation at alcohol metabolism genes ( ADH1B, ADH1C, ALDH2) and alcohol dependence in an American Indian population. 1288

Alcohol dehydrogenase (ADH; EC 1.1.1.1) and aldehyde dehydrogenase (ALDH; EC 1.2.1.3) have important roles in the elimination of ingested ethanol. These enzymes have polymorphisms resulting from single-point mutations that cause kinetic differences in their respective enzyme activities. Simultaneous observation of these enzymes would be useful in investigating the association between these enzyme polymorphisms and alcohol-related problems. In this study amplified genomic DNA was amplified from nail clippings with two sets of primers for ADH2 and ALDH2 genes, respectively, in a micro test tube and the accuracy of the amplification was verified by direct sequencing. The PCR products were separated into four distinct bands by single-strand conformation polymorphism analysis. This genotyping method is fast, accurate. reliable and inexpensive, and requires the same amount of template DNA as non-simultaneous methods. In other words, the required amount of template DNA for this method is only half that required for the separate genotyping of ADH2 and ALDH2.
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PMID:Simultaneous genotyping of alcohol dehydrogenase 2 and aldehyde dehydrogenase 2 by single-strand conformation polymorphism analysis. 1474 55

The toxicity of glycol ethers is associated with their oxidation to the corresponding aldehyde and alkoxyacetic acid by cytosolic alcohol dehydrogenase (ADH; EC 1.1.1.1.) and aldehyde dehydrogenase (ALDH; 1.2.1.3). Dermal exposure to these compounds can result in localised or systemic toxicity including skin sensitisation and irritancy, reproductive, developmental and haemotological effects. It has previously been shown that skin has the capacity for local metabolism of applied chemicals. Therefore, there is a requirement to consider metabolism during dermal absorption of these compounds in risk assessment for humans. Cytosolic fractions were prepared from rat liver, and whole and dermatomed skin by differential centrifugation. Rat skin cytosolic fractions were also prepared following multiple dermal exposure to dexamethasone, ethanol or 2-butoxyethanol (2-BE). The rate of ethanol, 2-ethoxyethanol (2-EE), ethylene glycol, 2-phenoxyethanol (2-PE) and 2-BE conversion to alkoxyacetic acid by ADH/ALDH in these fractions was continuously monitored by UV spectrophotometry via the conversion of NAD+ to NADH at 340 nm. Rates of ADH oxidation by rat liver cytosol were greatest for ethanol followed by 2-EE >ethylene glycol >2-PE >2-BE. However, the order of metabolism changed to 2-BE >2-PE >ethylene glycol >2-EE >ethanol using whole and dermatomed rat skin cytosolic fractions, with approximately twice the specific activity in dermatomed skin cytosol relative to whole rat skin. This suggests that ADH and ALDH are localised in the epidermis that constitutes more of the protein in dermatomed skin than whole skin cytosol. Inhibition of ADH oxidation in rat liver cytosol by pyrazole was greatest for ethanol followed by 2-EE >ethylene glycol >2-PE >2-BE, but it only inhibited ethanol metabolism by 40% in skin cytosol. Disulfiram completely inhibited alcohol and glycol ether metabolism in the liver and skin cytosolic fractions. Although ADH1, ADH2 and ADH3 are expressed at the protein level in rat liver, only ADH1 and ADH2 are selectively inhibited by pyrazole and they constitute the predominant isoforms that metabolise short-chain alcohols in preference to intermediate chain-length alcohols. However, ADH1, ADH3 and ADH4 predominate in rat skin, demonstrate different sensitivities to pyrazole, and are responsible for metabolising glycol ethers. ALDH1 is the predominant isoform in rat liver and skin cytosolic fractions that is selectively inhibited by disulfiram and responds to the amount of aldehyde formed by the ADH isoforms expressed in these tissues. Thus, the different affinity of ADH and ALDH for alcohols and glycol ethers of different carbon-chain length may reflect the relative isoform expression in rat liver and skin. Following multiple topical exposure, ethanol metabolism increased the most following ethanol treatment, and 2-BE metabolism increased the most following 2-BE treatment. Ethanol and 2-BE may induce specific ADH and ALDH isoforms that preferentially metabolise short-chain alcohols (i.e. ADH1, ALDH1) and longer chain alcohols (i.e. ADH3, ADH4, ALDH1), respectively. Treatment with a general inducing agent such as dexamethasone enhanced ethanol and 2-BE metabolism suggesting induction of multiple ADH isoforms.
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PMID:Cutaneous metabolism of glycol ethers. 1555 Oct 62

After a single oral dose of silodosin in male rats, male dogs and healthy human male volunteers, C(max) occurred within about 2 h, indicating rapid absorption. The elimination half-life was about 2 h in rat and dog, but 4.7 h (fasted) and 6.0 h (non-fasted) in humans. Absolute bioavailability values in rat, dog and human were about 9, 25 and 32%, respectively. In rat and dog, total blood clearance was almost equivalent to the hepatic blood flow, but that in human was low (20%), demonstrating a large species difference in hepatic clearance. In each species, the apparent volume of distribution exceeded the volume of total body water. After an oral dose of (14)C-silodosin to male rats, radioactivity was rapidly and widely distributed to most tissues. The highest concentrations outside the gastrointestinal tract were found in liver and kidney, with only low concentrations in brain tissues. The in vitro plasma protein binding of silodosin was about 80% in rat and dog, and 95.6% in humans, with alpha(1)-acid glycoprotein (AGP) contributing to the binding profile. Silodosin was found to be a dual substrate for CYP3A4 and p-glycoprotein. In human plasma, two major metabolites generated by UDP-glucuronosyltransferase (UGT; UGT2B7) and alcohol/aldehyde dehydrogenase (ADH/ALDH) were found, but no glucuronide conjugates were detected in rat or dog plasma. After a single oral dose of (14)C-silodosin in rat, dog and human, the urinary excretion of radioactivity was 15-34%, with that of unchanged silodosin being less than 4%. The radioactivity was predominantly excreted via the feces.
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PMID:[Pharmacokinetics and disposition of silodosin (KMD-3213)]. 1651 89

Using brain microdialysis, we measured both ethanol (EtOH) and acetaldehyde (AcH) levels in the striatum of free-moving rats following the inhibition of EtOH oxidation pathways. Rats received intraperitoneal EtOH (1g/kg) alone or in combination with 4-methylpyrazole (MP, 82 mg/kg, an alcohol dehydrogenase inhibitor), and/or catalase inhibitor sodium azide (AZ, 10mg/kg) or 3-amino-1,2,4-triazole (AT, 1g/kg), and/or cyanamide (CY, 50mg/kg, an aldehyde dehydrogenase inhibitor). Results revealed that both EtOH and AcH concentrations reached a plateau at 30 min after a dose of EtOH, and then gradually decreased for 4h. AcH was identified in the CY+EtOH, CY+AT/AZ+EtOH, and CY+4-MP+EtOH groups. The CY+EtOH-induced peak AcH level was 195.2+/-19.4 microM, and this level was significantly higher than the values in other groups studied. The catalase or ADH inhibitor in combination with CY lowered considerably the AcH concentration in the brain. The EtOH level reached a maximum of 25.9+/-2.3 mM in the CY+4-MP+EtOH group, and this level was markedly higher than in the EtOH group. No significant difference in brain EtOH levels was seen in any of the other groups examined. The findings strongly support the assumption that the enzyme catalase plays a significant role in AcH formation directly in the rat brain.
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PMID:Catalase mediates acetaldehyde formation in the striatum of free-moving rats. 1759 13

The genome of Natronomonas pharaonis encodes genes annotated as alcohol dehydrogenase (ADH; EC 1.1.1.1) and aldehyde dehydrogenase (ALDH; EC 1.2.1.3), enzymes involved in alcohol metabolism. These genes (adh and aldH2) occur in a single copy on the chromosome. We have studied the role of these genes in ethanol metabolism in N. pharaonis. Reverse transcription-PCR analysis showed that the aldH2 gene was inducible by ethanol, but the adh gene was transcribed both in the presence and absence of ethanol. The gene encoding for ALDH of N. pharaonis (NpALDH) was cloned into a pET41a vector containing a glutathione S-transferase tag, expressed in Escherichia coli and purified by glutathione sepharose affinity chromatography. The GST-NpALDH fusion protein was cleaved by bovine enterokinase and the target enzyme showed a molecular mass of approximately 60 kDa by SDS-PAGE. The enzyme was thermophilic and alkaliphilic, the optimal temperature and pH being 60 degrees C and 8.0, respectively. NpALDH was salt independent, being most active at 0.25 M NaCl or KCl.
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PMID:Aldehyde dehydrogenase of the haloalkaliphilic archaeon Natronomonas pharaonis and its function in ethanol metabolism. 1876 68

Class II alcohol dehydrogenase (pi-ADH), encoded by alcohol dehydrogenase (ADH4), is considered to contribute to ethanol (EtOH) oxidation in the liver at high concentration. Four single nucleotide polymorphisms (SNPs) were found in the promoter region of this gene. Analysis of genotype distribution in 102 unrelated Japanese subjects revealed that four loci were in strong linkage disequilibrium and could be classified into three haplotypes. The effects of these polymorphisms on transcriptional activity were investigated in HepG2 cells. Transcriptional activity was significantly higher in cells with the -136A allele than in those with the -136C allele. To investigate whether this difference in transcriptional activity caused a difference in EtOH elimination, previous data on blood EtOH changes after 0.4 g/kg body weight alcohol ingestion were analyzed. When analyzed based on aldehyde dehydrogenase-2 gene (ALDH2) (487)Glu/Lys genotype, the significantly lower level of EtOH at peak in subjects with -136C/A and -136A/A genotype compared with subjects with -136C/C genotype indicated that -136 bp was a suggestive locus for differences in EtOH oxidation. This effect was observed only in subjects with ALDH2 (487)Glu/Glu. These results suggested that the SNP at -136bp in the ADH4 promoter had an effect on transcriptional regulation, and that the higher activity of the -136A allele compared with the -136C allele caused a lower level of blood EtOH after alcohol ingestion; that is, individuals with the -136A allele may consume more EtOH and might have a higher risk for development of alcohol dependence than those without the -136A allele.
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PMID:Polymorphisms in the promoter region of the human class II alcohol dehydrogenase (ADH4) gene affect both transcriptional activity and ethanol metabolism in Japanese subjects. 1918 38

In bioelectrocatalysis, nanomaterials are typically used as a conductive bridge for the gap between the site of oxidation/reduction (i.e., enzymatic biocatalyst) and the current collector (electrode). In this paper, carbon nanomaterial supports have been employed in conjunction with heme-c containing pyrroloquinoline quinone-dependent alcohol dehydrogenase (PQQ-ADH) and aldehyde dehydrogenase (PQQ-AldDH) oxidoreductase enzymes as oxidation catalysts to produce stable high surface area catalyst supports for the bioelectrocatalysis of ethanol in biofuel cells. The structure of PQQ-ADH and PQQ-AldDH allow for direct electron transfer (DET) between the enzymes and carbon nanomaterial support without the use of additional charge carrying chemical mediators. In this paper, the employment of nanomaterials are used to produce stable, high surface area catalyst supports which aid in enzyme adsorption and direct electron transfer. Fundamental DET studies were performed on both PQQ-ADH and PQQ-AldDH in order to understand the processes occurring at the electrode surface. Data shows a direct correlation between concentration of substrate and peak potential and peak current. Incorporating nanotubes into this technology has allowed an increase in the current density of ethanol/air biofuel cells by up to 14.5 fold and increased the power density by up to 18.0 fold.
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PMID:Bioelectrocatalysis of ethanol via PQQ-dependent dehydrogenases utilizing carbon nanomaterial supports. 1943 78

The present study investigated the effect of fenugreek seed polyphenolic extract (FPEt) on ethanol-induced protein expression in Chang liver cells. Cells were incubated with either 30 mM EtOH alone or together in the presence of FPEt for 24 h. Cells were harvested and assessed for expression of alcohol metabolizing enzymes-alcohol dehydrogenase (ADH(2) isoform), aldehyde dehydrogenase (ALDH(2) isoform), cytochrome P450 (CYP2E1), the electron transport component (cytochrome-c), and the heat shock proteins. The expression of ADH(2), ALDH(2), and CYP2E1 were upregulated, whereas the expression of cytochrome-c was downregulated in the ethanol-treated cells. The expression of cellular heat shock proteins-HSP70, HSC70, HSC92, and mitochondrial protein mtHSP70 were induced in ethanol-treated Chang liver cells. FPEt modulated the protein expression changes induced by ethanol and had no effect when incubated with normal Chang liver cells. FPEt might exert cytoprotective action on ethanol-induced liver cell damage, possibly by enhancing cellular redox status.
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PMID:Induction of alcohol-metabolizing enzymes and heat shock protein expression by ethanol and modulation by fenugreek seed polyphenols in Chang liver cells. 1977 55

Until 200 years ago, methanol was an extremely rare component of the human diet and is still rarely consumed in contemporary hunter and gatherer cultures. With the invention of canning in the 1800s, canned and bottled fruits and vegetables, whose methanol content greatly exceeds that of their fresh counterparts, became far more prevalent. The recent dietary introduction of aspartame, an artificial sweetener 11% methanol by weight, has also greatly increased methanol consumption. Moreover, methanol is a major component of cigarette smoke, known to be a causative agent of many diseases of civilization (DOC). Conversion to formaldehyde in organs other than the liver is the principal means by which methanol may cause disease. The known sites of class I alcohol dehydrogenase (ADH I), the only human enzyme capable of metabolizing methanol to formaldehyde, correspond to the sites of origin for many DOC. Variability in sensitivity to exogenous methanol consumption may be accounted for in part by the presence of aldehyde dehydrogenase sufficient to reduce the toxic effect of formaldehyde production in tissue through its conversion to the much less toxic formic acid. The consumption of small amounts of ethanol, which acts as a competitive inhibitor of methanol's conversion to formaldehyde by ADH I, may afford some individuals protection from DOC.
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PMID:Methanol: a chemical Trojan horse as the root of the inscrutable U. 1989 82


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