Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027497 (nausea)
 23,468 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Differences in the pharmacokinetics of alcohol absorption and elimination are, in part, genetically determined. There are polymorphic variants of the two main enzymes responsible for ethanol oxidation in liver, alcohol dehydrogenase and aldehyde dehydrogenase. The frequency of occurrence of these variants, which have been shown to display strikingly different catalytic properties, differs among different racial populations. Since the activity of alcohol dehydrogenase in liver is a rate-limiting factor for ethanol metabolism in experimental animals, it is likely that the type and content of the polymorphic isoenzyme subunit encoded at ADH2, beta-subunit, and at ADH3, the gamma-subunit, are contributing factors to the genetic variability in ethanol elimination rate. The recent development of methods for genotyping individuals at these loci using white cell DNA will allow us to test this hypothesis as well as any relationship between ADH genotype and the susceptibility to alcoholism or alcohol-related pathology. A polymorphic variant of human liver mitochondrial aldehyde dehydrogenase, ADLH2, which has little or no acetaldehyde oxidizing activity has been identified. Individuals with the deficient ALDH2 phenotype do not have altered ethanol elimination rates but they do exhibit high blood acetaldehyde levels and dysphoric symptoms such as facial flushing, nausea and tachycardia, after drinking alcohol. Because acetaldehyde is so reactive, it binds to free amino groups of proteins including a 37 kilodalton hepatic protein-acetaldehyde adduct and may elicit an antibody response. We would predict that individuals who have low ALDH2 activity because of liver disease or because they have the inactive ALDH2 variant isoenzyme might form more protein-acetaldehyde adducts and elicit a greater immune response. These adducts may represent good biological markers of alcohol abuse and may also play a role in liver injury due to chronic alcohol consumption.
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PMID:Genetic polymorphism of enzymes of alcohol metabolism and susceptibility to alcoholic liver disease. 306 25

Sulfiram, a drug applied topically to treat scabies, produces effects similar to those of disulfiram after subsequent ingestion of ethanol. Disulfiram, used in aversion therapy in the treatment of alcoholism, inhibits hepatic aldehyde dehydrogenase (ALDH) causing an accumulation of acetaldehyde after ethanol ingestion. The increased tissue levels of acetaldehyde cause a spectrum of undesirable side-effects including flushing, nausea, vomiting, and tachycardia, which are referred to as the disulfiram reaction. Previous studies have shown that in vitro sulfiram is a very weak inhibitor of ALDH, but solutions of sulfiram markedly increase in potency with time. In the present study, fresh solutions of sulfiram were exposed to fluorescent room light under ambient conditions and analyzed at timed intervals by HPLC. At least eight products, including disulfiram, were formed in the light-exposed sulfiram solutions, but not in solutions kept in the dark. Structural characterization of two of the photolysis products was obtained by on-line microbore HPLC-mass spectrometry (mu LC-MS) and on-line microbore HPLC-tandem mass spectrometry (mu LC-MS/MS) using continuous flow-liquid secondary ion mass spectrometry (CF-LSIMS) as the primary ionization method. Sulfiram was converted to disulfiram at an initial rate of 0.7%/hr, and the formation of disulfiram correlated with the increase in ALDH inhibition in vitro. The results of this investigation show that while sulfiram is a weak inhibitor of ALDH in vitro, it is readily photoconverted to disulfiram, a very potent inhibitor of ALDH, which may explain the adverse reaction to ethanol after sulfiram therapy.
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PMID:Photolysis of sulfiram: a mechanism for its disulfiram-like reaction. 798 3

Chagas' disease (American trypanosomiasis) is an endemic parasitic disease in some areas of Latin America. About 16-18 million persons are infected with the aetiological agent of the disease, Trypanosoma cruzi, and more than 100 million are living at risk of infection. There are different modes of infection: (1) via blood sucking vector insects infected with T. cruzi, accounting for 80-90% of transmission of the disease; (2) via blood transfusion or congenital transmission, accounting for 0.5-8% of transmission; (3) other less common forms of infection, eg, from infected food or drinks or via infected organs used in transplants. The acute phase of the disease can last from weeks to months and typically is asymptomatic or associated with fever and other mild nonspecific manifestations. However, life-threatening myocarditis or meningoencephalitis can occur during the acute phase. The death rate for persons in this phase is about 10%. Approximately 10-50% of the survivors develop chronic Chagas' disease, which is characterized by potentially lethal cardiopathy and megacolon or megaoesophagus. There are two drugs available for the aetiological treatment of Chagas' disease: nifurtimox (Nfx) and benznidazole (Bz). Nfx is a nitrofurane and Bz is a nitroimidazole compound. The use of these drugs to treat the acute phase of the disease is widely accepted. However, their use in the treatment of the chronic phase is controversial. The undesirable side effects of both drugs are a major drawback in their use, frequently forcing the physician to stop treatment. The most frequent adverse effects observed in the use of Nfx are: anorexia, loss of weight, psychic alterations, excitability, sleepiness, digestive manifestations such as nausea or vomiting, and occasionally intestinal colic and diarrhoea. In the case of Bz, skin manifestations are the most notorious (e.g., hypersensitivity, dermatitis with cutaneous eruptions, generalized oedema, fever, lymphoadenopathy, articular and muscular pain), with depression of bone marrow, thrombocytopenic purpura and agranulocytosis being the more severe manifestations. Experimental toxicity studies with Nfx evidenced neurotoxicity, testicular damage, ovarian toxicity, and deleterious effects in adrenal, colon, oesophageal and mammary tissue. In the case of Bz, deleterious effects were observed in adrenals, colon and oesophagus. Bz also inhibits the metabolism of several xenobiotics biotransformed by the cytochrome P450 system and its reactive metabolites react with fetal components in vivo. Both drugs exhibited significant mutagenic effects and were shown to be tumorigenic or carcinogenic in some studies. The toxic side effects of both nitroheterocyclic derivatives require enzymatic reduction of their nitro group. Those processes are fundamentally mediated by cytochrome P450 reductase and cytochrome P450. Other enzymes such as xanthine oxidoreductase or aldehyde oxidase may also be involved.
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PMID:Toxic side effects of drugs used to treat Chagas' disease (American trypanosomiasis). 1693 19

Disulfiram (Antabuse) is used for aversive treatment of alcohol dependence with good effects. Through inhibition of aldehyde dehydrogenase, disulfiram heightens serum aldehyde concentration after alcohol ingestion and causes aversive disulfiram-ethanol reaction. Typical symptoms of this reaction include flushing, nausea, dyspnea, tremor, and confusion, which are usually self-limiting. However, severe life-threatening arterial hypotension sometimes develops. We report here a patient with generalized flushing, tremor, and refractive hypotension after ingestion of alcohol 18 hours after disulfiram treatment. Initial volume resuscitation and dopamine infusion failed to restore the blood pressure. Noradrenaline was given and the blood pressure returned to normal range. This case illustrates the intensity of disulfiram-ethanol reaction and underscores the advantageous use of noradrenaline in patients in such a critical condition.
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PMID:Refractive hypotension in a patient with disulfiram-ethanol reaction. 1722 Jun 94

Liver alcohol dehydrogenase oxidizes ethanol to acetaldehyde, which is further oxidized to acetate by aldehyde dehydrogenase-2 (ALDH2*1). Individuals who carry a low-activity ALDH2 (ALDH2*2) display high blood acetaldehyde levels after ethanol consumption, which leads to dysphoric effects, such as facial flushing, nausea, dizziness, and headache ("Asian alcohol phenotype"), which result in an aversion to alcohol and protection against alcohol abuse and alcoholism. Mimicking this phenotype may reduce alcohol consumption in alcoholics. RNA interference (RNAi) is a cell process in which a short interfering RNA (siRNA) of 21-25 bp guides the degradation of a complementary target mRNA. Thus, siRNAs may be useful in mimicking the Asian phenotype by inhibiting ALDH2 gene expression. We determined the inhibitory effect of three chemically synthesized siRNAs targeted against rat ALDH2 mRNA in human embryonic kidney cells (HEK-293 cell lines) transfected with a plasmid carrying the rat ALDH2 cDNA. Two of the three siRNAs were active, yielding a 65-75% reduction of ALDH2 activity. Based on the most promising siRNA sequence, three short hairpin RNA (shRNA) genes driven by the human U6 RNA promoter were designed and cloned in a plasmid. After transfection of HEK-293 cells, one of the genes was shown to be active, yielding a 50% reduction of ALDH2 activity. This effect is consistent with a 50% reduction in ALDH2 mRNA, whereas neither beta-actin mRNA nor the interferon-inducible transmembrane protein-1 mRNA levels were affected. This study describes chemically synthesized siRNAs and an endogenously synthesized shRNA, which reduce ALDH2 activity and constitute tools that should be of value for further alcohol research.
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PMID:RNA interference against aldehyde dehydrogenase-2: development of tools for alcohol research. 1925 Nov 11

Disulfiram treatment for alcohol dependence is used with acceptable outcomes. By inhibiting the aldehyde dehydrogenase enzyme, this treatment increases acetaldehyde concentration after the ingestion of alcohol causing an unpleasant disulfiram-alcohol reaction. Typical symptoms include flushing, headache, nausea, vomiting, sweating, vertigo, and lightheadedness. However, there have also been descriptions of more serious reactions including severe hypotension, arrhythmias, myocardial infarction, and cardiovascular collapse. We report a patient with a severe disulfiram-alcohol reaction marked by flushing, confusion, generalized malaise, epigastric pain, and hypotension. Cardiac biomarker and electrocardiographic changes were suggestive of non-ST-elevation myocardial infarction (NSTEMI). Left heart catheterization showed no angiographic evidence of coronary artery disease. Because of the frequency of alcohol dependence and its treatment with disulfiram, it is critical for physicians to be aware of these types of life-threatening complications.
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PMID:Disulfiram--alcohol reaction mimicking an acute coronary syndrome. 2474 56

Alcohol drinking increases the risk for a number of cancers. Currently, the highest risk (Group 1) concerns oral cavity, pharynx, larynx, esophagus, liver, colorectum, and female breast, as assessed by the International Agency for Research on Cancer (IARC). Alcohol and other beverage constituents, their metabolic effects, and alcohol-related unhealthy lifestyles have been suggested as etiological factors. The aim of the present survey is to evaluate the carcinogenic role of acetaldehyde in alcohol-related cancers, with special emphasis on the genetic-epidemiological evidence. Acetaldehyde, as a constituent of alcoholic beverages, and microbial and endogenous alcohol oxidation well explain why alcohol-related cancers primarily occur in the digestive tracts and other tissues with active alcohol and acetaldehyde metabolism. Genetic-epidemiological research has brought compelling evidence for the causality of acetaldehyde in alcohol-related cancers. Thus, IARC recently categorized alcohol-drinking-related acetaldehyde to Group 1 for head and neck and esophageal cancers. This is probably just the tip of the iceberg, since more recent epidemiological studies have also shown significant positive associations between the aldehyde dehydrogenase ALDH2 (rs671)*2 allele (encoding inactive enzyme causing high acetaldehyde elevations) and gastric, colorectal, lung, and hepatocellular cancers. However, a number of the current studies lack the appropriate matching or stratification of alcohol drinking in the case-control comparisons, which has led to erroneous interpretations of the data. Future studies should consider these aspects more thoroughly. The polymorphism phenotypes (flushing and nausea) may provide valuable tools for future successful health education in the prevention of alcohol-drinking-related cancers.
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PMID:Genetic-epidemiological evidence for the role of acetaldehyde in cancers related to alcohol drinking. 2542

Alcohol consumption often leads to hangover, a condition characterized by several symptoms, characteristically headache, nausea, fatigue and drowsiness. Hangover may be alleviated by altering the rate of alcohol metabolism and facilitating elimination of acetaldehyde by affecting the activity of alcohol dehydrogenase (ADH) and/or aldehyde dehydrogenase (ALDH) enzymes. In the present study, several food commodities like fruits, vegetables, cereals, pulses, dairy products, spices and other miscellaneous products (ascorbic acid, cocoa sample, tea, coffee, egg yolk and date samples) were investigated for their effect on the in vitro activities of the enzymes and their antioxidant properties. Of the many screened food commodities, few showed an increase in the activity of either one or both the enzymes, ADH and ALDH. Studies showed no correlation between ADH and ALDH enzyme activities and antioxidant property of the selected food commodities for anti-hangover effect. Further, an anti-hangover (AHO) product was developed using pear (65%), sweet lime (25%) and coconut water (10%) and, validated for in vitro ADH and ALDH enzyme activities. AHO product was found to enhance ADH and ALDH activities by 23.31% and 70.02%, respectively.
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PMID:Influence of food commodities on hangover based on alcohol dehydrogenase and aldehyde dehydrogenase activities. 3291