RESUMEN
AIMS: To mimic, in an animal model of alcoholism, the protective phenotype against alcohol consumption observed in humans carrying a fast alcohol dehydrogenase (ADH1B*2) and an inactive aldehyde dehydrogenase (ALDH2*2). METHODS: We developed a multiple expression cassette adenoviral vector (AdV-ADH/asALDH2) encoding both a fast rat ADH and an antisense RNA against rat ALDH2. A control adenoviral vector (AdV-C) containing intronic non-coding DNA was also developed. These adenoviral vectors were administered intravenously to rats bred as high alcohol-drinkers (University of Chile bibulous) that were previously rendered alcohol dependent by a 75-day period of voluntary 10% ethanol intake. RESULTS: Animals administered AdV-ADH/asALDH2 showed a 176% increase in liver ADH activity, whereas liver ALDH2 activity was reduced by 24%, and upon the administration of a dose of ethanol (1 g/kg, i.p.), these showed arterial acetaldehyde levels that were 400% higher than those of animals administered AdV-C. Rats that received the AdV-ADH/asALDH2 vector reduced by 60% their voluntary ethanol intake versus controls. CONCLUSION: This study provides evidence that the simultaneous increase of liver ADH and a reduction of ALDH activity by gene transfer could constitute a potential therapeutic strategy for the treatment of alcoholism.
Asunto(s)
Alcohol Deshidrogenasa/genética , Consumo de Bebidas Alcohólicas/genética , Alcoholismo/terapia , Aldehído Deshidrogenasa/antagonistas & inhibidores , Técnicas de Transferencia de Gen/psicología , Vectores Genéticos/uso terapéutico , Proteínas Mitocondriales/antagonistas & inhibidores , ARN sin Sentido/uso terapéutico , Acetaldehído/sangre , Adenoviridae/genética , Alcohol Deshidrogenasa/metabolismo , Consumo de Bebidas Alcohólicas/sangre , Consumo de Bebidas Alcohólicas/metabolismo , Alcoholismo/sangre , Alcoholismo/genética , Alcoholismo/metabolismo , Aldehído Deshidrogenasa/genética , Aldehído Deshidrogenasa Mitocondrial , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Femenino , Isoenzimas/genética , Isoenzimas/metabolismo , Hígado/metabolismo , Proteínas Mitocondriales/genética , ARN sin Sentido/genética , Ratas , Ratas WistarRESUMEN
Epidemiologic studies addressing the association of alcohol consumption with breast cancer consistently suggest a modest association and a dose-response relationship. The epidemiologic evidence does not point to a single mechanism to explain the association, and several mechanisms have been proposed. Alcohol consumption is shown to increase levels of endogenous estrogens, known risk factors for breast cancer. This hypothesis is further supported by data showing that the alcohol-breast cancer association is limited to women with estrogen-receptor positive tumors. Products of alcohol metabolism are known to be toxic and are hypothesized to cause DNA modifications that lead to cancer. Recent research has focused on genes that influence the rate of alcohol metabolism, with genes that raise blood concentrations of acetaldehyde hypothesized to heighten breast cancer risk. Mounting evidence suggests that antioxidant intake(e.g.folate)mayreducealcohol-associatedbreast cancer risk, because it neutralizes reactive oxygen species, a second-stage product of alcohol metabolism. Diets lacking sufficient antioxidant intake, as a result, may further elevate the risk of breast cancer among alcohol consumers. Given that alcohol consumption is increasing worldwide and especially among women in countries of rapid economic growth, a greater understanding of the mechanisms underlying the known alcohol-breast cancer association is warranted.Avoiding overconsumption of alcohol is recommended, especially for women with known risk factors for breast cancer.
Diversos estudios epidemiológicos muestran la asociación del consumo de alcohol con el cáncer de mama de forma consistente, lo que sugiere una modesta asociación, y una relación de dosis-respuesta.La evidencia no apunta a un mecanismo único para explicar la asociación y varios mecanismos han sido propuestos. El consumo de alcohol incrementa los niveles endógenos de estrógeno, un riesgo conocido para cáncer de mama. Esta hipótesis es apoyada por información que muestra que la asociación entre el alcohol y el cáncer de mama está limitada a mujeres con tumores con receptores positivos de estrógeno. Es conocido que los derivados de la metabolización del alcohol son tóxicos, y se ha pensado que causan modificaciones en el DNA que llevan al cáncer. La investigación reciente se ha enfocado en genes que influencian la velocidad con la que se metaboliza el alcohol, y elevan las concentraciones de acetaldehído que se piensa puede aumentar el riesgo de cáncer de mama. La evidencia actual sugiere que la ingesta de antioxidantes (e.g. folato) puede reducirelriesgode cáncer asociadoalalcohol,porque neutraliza las especies reactivas de oxígeno, un producto de la segunda etapa del metabolismo del alcohol. Las dietas con ingesta insuficiente de antioxidantes,como resultado de esto, pueden elevar el riesgo de cáncer entre los consumidores de alcohol.Dado que el consumo de alcohol está incrementando en todo el mundo, especialmente en mujeres de países con rápido crecimiento económico, un mejor entendimiento de los mecanismos subyacentes a la asociación del cáncer de mama y el alcohol es necesario. Evitar el consumo excesivo es recomendado, especialmente para mujeres con factores de riesgo conocidos para cáncer de mama.
Asunto(s)
Femenino , Humanos , Consumo de Bebidas Alcohólicas/epidemiología , Neoplasias de la Mama/epidemiología , Acetaldehído/efectos adversos , Acetaldehído/sangre , Antioxidantes , Biotransformación , Neoplasias de la Mama/etiología , Cocarcinogénesis , Daño del ADN , Dieta , Ingestión de Energía , Estrógenos , Etanol/efectos adversos , Etanol/farmacocinética , Menopausia , México/epidemiología , Modelos Biológicos , Neoplasias Hormono-Dependientes/epidemiología , Neoplasias Hormono-Dependientes/etiología , RiesgoRESUMEN
The main goal of this study was to investigate the ability of an ethanol dose (1g/kg) administered intraperitoneally to induce conditioned place preference (CPP) and/or conditioned place aversion (CPA) in two lines of rats selectively bred for their high (UChB) or low (UChA) voluntary ethanol intake. It was found that five pairings with ethanol induced CPA in ethanol-naïve rats of both lines, but the magnitude of avoidance was lower in the UChB relative to the UChA rats, indicating that ethanol was less aversive to naïve rats bred for high alcohol drinking. After 2 months of high voluntary ethanol drinking (~6-7g/kg/day), in free choice between 10% ethanol and water, ethanol produced CPP in UChB rats, reflecting that ethanol had become rewarding to these rats. By contrast, the low voluntary ethanol intake (<1g/kg/day) displayed by UChA rats preexposed for 2 months in free choice did not change ethanol-induced CPA. However, preexposure of UChA rats to forced ethanol drinking (~5.7g/kg/day) and the later inhibition of ethanol-derived acetaldehyde by 4-methylpyrazole (10mg/kg intraperitoneal), an inhibitor of the enzyme alcohol dehydrogenase, not only increased their voluntary ethanol intake in free choice, but also had a facilitating effect on the development of CPP. Taken together, these results show that the expression of the reinforcing effects of ethanol required a period of voluntary ethanol intake in UChB rats, whereas in UChA rats, both prior exposure to forced ethanol drinking and reduction of high blood ethanol-derived acetaldehyde were required.
Asunto(s)
Consumo de Bebidas Alcohólicas/psicología , Condicionamiento Psicológico , Etanol/administración & dosificación , Acetaldehído/sangre , Aldehído Deshidrogenasa/antagonistas & inhibidores , Animales , Cruzamiento , Inhibidores Enzimáticos/administración & dosificación , Femenino , Fomepizol , Pirazoles/administración & dosificación , Ratas , Refuerzo en Psicología , Autoadministración/veterinariaRESUMEN
Epidemiologic studies addressing the association of alcohol consumption with breast cancer consistently suggest a modest association and a dose-response relationship. The epidemiologic evidence does not point to a single mechanism to explain the association, and several mechanisms have been proposed. Alcohol consumption is shown to increase levels of endogenous estrogens, known risk factors for breast cancer. This hypothesis is further supported by data showing that the alcohol-breast cancer association is limited to women with estrogen-receptor positive tumors. Products of alcohol metabolism are known to be toxic and are hypothesized to cause DNA modifications that lead to cancer. Recent research has focused on genes that influence the rate of alcohol metabolism, with genes that raise blood concentrations of acetaldehyde hypothesized to heighten breast cancer risk. Mounting evidence suggests that antioxidant intake(e.g.folate)mayreducealcohol-associatedbreast cancer risk, because it neutralizes reactive oxygen species, a second-stage product of alcohol metabolism. Diets lacking sufficient antioxidant intake, as a result, may further elevate the risk of breast cancer among alcohol consumers. Given that alcohol consumption is increasing worldwide and especially among women in countries of rapid economic growth, a greater understanding of the mechanisms underlying the known alcohol-breast cancer association is warranted. Avoiding overconsumption of alcohol is recommended, especially for women with known risk factors for breast cancer.
Asunto(s)
Consumo de Bebidas Alcohólicas/epidemiología , Neoplasias de la Mama/epidemiología , Acetaldehído/efectos adversos , Acetaldehído/sangre , Antioxidantes , Biotransformación , Neoplasias de la Mama/etiología , Cocarcinogénesis , Daño del ADN , Dieta , Ingestión de Energía , Estrógenos , Etanol/efectos adversos , Etanol/farmacocinética , Femenino , Humanos , Menopausia , México/epidemiología , Modelos Biológicos , Neoplasias Hormono-Dependientes/epidemiología , Neoplasias Hormono-Dependientes/etiología , RiesgoRESUMEN
Humans who carry a point mutation in the gene coding for alcohol dehydrogenase-1B (ADH1B*2; Arg47His) are markedly protected against alcoholism. Although this mutation results in a 100-fold increase in enzyme activity, it has not been reported to cause higher levels of acetaldehyde, a metabolite of ethanol known to deter alcohol intake. Hence, the mechanism by which this mutation confers protection against alcoholism is unknown. To study this protective effect, the wild-type rat cDNA encoding rADH-47Arg was mutated to encode rADH-47His, mimicking the human mutation. The mutated cDNA was incorporated into an adenoviral vector and administered to genetically selected alcohol-preferring rats. The V(max) of rADH-47His was 6-fold higher (P<0.001) than that of the wild-type rADH-47Arg. Animals transduced with rAdh-47His showed a 90% (P<0.01) increase in liver ADH activity and a 50% reduction (P<0.001) in voluntary ethanol intake. In animals transduced with rAdh-47His, administration of ethanol (1g/kg) produced a short-lived increase of arterial blood acetaldehyde concentration to levels that were 3.5- to 5-fold greater than those in animals transduced with the wild-type rAdh-47Arg vector or with a noncoding vector. This brief increase (burst) in arterial acetaldehyde concentration after ethanol ingestion may constitute the mechanism by which humans carrying the ADH1B*2 allele are protected against alcoholism.
Asunto(s)
Alcohol Deshidrogenasa/genética , Alcoholismo/enzimología , Alcoholismo/prevención & control , Acetaldehído/sangre , Adenoviridae/genética , Alcohol Deshidrogenasa/metabolismo , Alcoholismo/genética , Alelos , Sustitución de Aminoácidos , Animales , Animales Modificados Genéticamente , Secuencia de Bases , Línea Celular , Cartilla de ADN/genética , Modelos Animales de Enfermedad , Etanol/administración & dosificación , Vectores Genéticos , Humanos , Cinética , Mutagénesis Sitio-Dirigida , Mutación Puntual , Polimorfismo Genético , Ratas , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transducción Genética , TransfecciónRESUMEN
BACKGROUND: Disulfiram, an inhibitor of aldehyde dehydrogenase used in the treatment of alcoholism, is an effective medication when its intake is supervised by a third person. However, its therapeutic efficacy varies widely, in part due to the fact that disulfiram is a pro-drug that requires its transformation into an active form and because it shows a wide range of secondary effects which often prevent the use of doses that ensure full therapeutic effectiveness. In this preclinical study in rats we report the development of tolerance to disulfiram induced by the chronic ingestion of ethanol, an additional source of variation for the actions of disulfiram with possible therapeutic significance, We also addresses the likely mechanism of this effect. METHODS: Wistar-derived rats bred for generations as high ethanol drinkers (UChB) were trained for either 3 days (Group A) or 30 days (Group B) to choose between ethanol (10% v/v) or water, which were freely available from 2 bottles on a 24-hour basis. Subsequently, animals in both groups were administered disulfiram or cyanamide (another inhibitor of aldehyde dehydrogenase) and ethanol intake in this free choice paradigm was determined. Animals were also administered a standard dose of 1 g ethanol/kg (i.p) and arterial blood acetaldehyde was measured. RESULTS: Disulfiram (12.5 and 25 mg/kg) and cyanamide (10 mg/kg) markedly inhibited ethanol intake (up to 60 to 70%) in animals that had ethanol access for only 3 days (Group A). However both drugs were inactive in inhibiting ethanol intake in animals that had consumed ethanol for 30 days (Group B). Following the injection of 1 g ethanol/kg, arterial blood acetaldehyde levels reached levels of 150 and 300 microM for disulfiram and cyanamide respectively, values which were virtually identical regardless of the length of prior ethanol intake of the animals. CONCLUSIONS: Chronic ethanol intake in high-drinker rats leads to marked tolerance to the aversive effects of disulfiram and cyanamide on ethanol intake despite the presence of consistently high levels of blood acetaldehyde. These findings may have implications for the use of disulfiram for the treatment of alcoholism in humans.
Asunto(s)
Disuasivos de Alcohol/farmacología , Consumo de Bebidas Alcohólicas/tratamiento farmacológico , Disulfiram/farmacología , Tolerancia a Medicamentos , Etanol/administración & dosificación , Acetaldehído/sangre , Alcohol Deshidrogenasa/antagonistas & inhibidores , Alcoholismo/tratamiento farmacológico , Animales , Cianamida/farmacología , Cianamida/uso terapéutico , Disulfiram/uso terapéutico , Inhibidores Enzimáticos/farmacología , Femenino , Ratas , Ratas WistarRESUMEN
Individuals who carry the most active alcohol dehydrogenase (ADH) isoforms are protected against alcoholism. This work addresses the mechanism by which a high ADH activity leads to low ethanol intake in animals. Male and female ethanol drinker rats (UChB) were allowed access to 10% ethanol for 1 h. Females showed 70% higher hepatic ADH activity and displayed 60% lower voluntary ethanol intake than males. Following ethanol administration (1 g/kg ip), females generated a transient blood acetaldehyde increase ("burst") with levels that were 2.5-fold greater than in males (P < 0.02). Castration of males led to 1) an increased ADH activity (+50%, P < 0.001), 2) the appearance of an acetaldehyde burst (3- to 4-fold vs. sham), and 3) a reduction of voluntary ethanol intake comparable with that of naïve females. The ADH inhibitor 4-methylpyrazole blocked the appearance of arterial acetaldehyde and increased ethanol intake. Since the release of NADH from the ADH.NADH complex constitutes the rate-limiting step of ADH (but not of ALDH2) activity, endogenous NADH oxidizing substrates present at the time of ethanol intake may contribute to the acetaldehyde burst. Sodium pyruvate given at the time of ethanol administration led to an abrupt acetaldehyde burst and a greatly reduced voluntary ethanol intake. Overall, a transient surge of arterial acetaldehyde occurs upon ethanol administration due to 1) high ADH levels and 2) available metabolites that can oxidize hepatic NADH. The acetaldehyde burst is strongly associated with a marked reduction in ethanol intake.
Asunto(s)
Acetaldehído/sangre , Alcohol Deshidrogenasa/genética , Alcohol Deshidrogenasa/metabolismo , Consumo de Bebidas Alcohólicas/genética , Etanol/farmacología , Caracteres Sexuales , Acetaldehído/metabolismo , Consumo de Bebidas Alcohólicas/sangre , Consumo de Bebidas Alcohólicas/metabolismo , Animales , Etanol/sangre , Femenino , Hígado/enzimología , Hígado/metabolismo , Masculino , Orquiectomía , Ratas , Ratas WistarRESUMEN
Because of the important glutamatergic mediation of the behavioral effects of ethanol, glutamatergic agents have attracted attention for the treatment of ethanol abuse and dependence in preclinical and clinical studies. In the present study, we investigated the effect of pharmacological doses of the natural polyamines putrescine, spermine, and spermidine and the synthetic polyamine N,N'-bis-(3-aminopropyl)cyclohexane-1,4-diamine (DCD) on alcohol consumption in a free-choice paradigm carried out in genetically high-ethanol-consumer UChB rats. Short 3-day treatment with either polyamine, administered p.o., significantly reduced ethanol intake without modifying water and food intakes. Neither polyamine was able to increase markedly blood acetaldehyde in rats submitted to a standard challenge dose of ethanol, to rule out a disulfiram-like effect. Besides, blood ethanol disappearance after a test dose of ethanol was not affected by the synthetic polyamine DCD. Long-term treatment with DCD dose-dependently reduced ethanol intake in UChB rats without producing any observable effect on overt behavior, food consumption, and total fluid intake. The present results indicate that pharmacological doses of polyamines can reduce ethanol consumption in genetically drinking rats without producing significant side effects, suggesting that modulation of brain N-methyl-d-aspartate receptors by polyamines could represent a suitable strategy to reduce appetite for ethanol. However, caution must be exercised in interpreting the results because polyamines can also affect neuronal excitability by acting at other receptor targets, such as AMPA and kainate receptors, as well as at some voltage-dependent ion channels.
Asunto(s)
Disuasivos de Alcohol , Consumo de Bebidas Alcohólicas/psicología , Ciclohexanos/farmacología , Poliaminas/farmacología , Acetaldehído/sangre , Consumo de Bebidas Alcohólicas/genética , Animales , Poliaminas Biogénicas/farmacología , Disulfiram/farmacología , Relación Dosis-Respuesta a Droga , Ingestión de Líquidos/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Femenino , Masculino , Ratas , Ratas Endogámicas , Receptores de N-Metil-D-Aspartato/efectos de los fármacosRESUMEN
Dependence on alcohol, a most widely used drug, has a heritability of 50-60%. Wistar-derived rats selectively bred as low-alcohol consumers for many generations present an allele (Aldh2(2)) of mitochondrial aldehyde dehydrogenase that does not exist in high-alcohol consumers, which mostly carry the Aldh2(1) allele. The enzyme coded by Aldh2(2) has a four- to five-fold lower affinity for NAD than that coded by Aldh2(1). The present study was designed to determine whether these polymorphisms account for differences in voluntary ethanol intake and to investigate the biological mechanisms involved. Low-drinker F0 Aldh2(2)/Aldh2(2) rats were crossed with high-drinker F0 Aldh2(1)/Aldh2(1) rats to obtain an F1 generation, which was intercrossed to obtain an F2 generation that segregates the Aldh2 alleles from other genes that may have been coselected in the breeding for each phenotype. Data show that, with a mixed genetic background, F2 Aldh2(1)/Aldh2(1) rats voluntarily consume 65% more alcohol (P<0.01) than F2 Aldh2(2)/Aldh2(2) rats. A major phenotypic difference was a five-fold higher (P<0.0025) peak blood acetaldehyde level following ethanol administration in the lower drinker F2 Aldh2(2)/Aldh2(2) compared to the higher drinker F2 Aldh2(1)/Aldh2(1) animals, despite the existence of identical steady-state levels of blood acetaldehyde in animals of both genotypes. Polymorphisms in Aldh2 play an important role in: (i) determining peak blood acetaldehyde levels and (ii) modulating voluntary ethanol consumption. We postulate that the markedly higher peak of blood acetaldehyde generated in Aldh2(2)/Aldh2(2)(2) animals is aversive, leading to a reduced alcohol intake in Aldh2(2)/Aldh2(2) versus that in Aldh2(1)/Aldh2(1) animals.
Asunto(s)
Acetaldehído/sangre , Aldehído Deshidrogenasa/genética , Etanol/administración & dosificación , Mitocondrias/enzimología , Polimorfismo Genético , Animales , Femenino , Genotipo , Masculino , Fenotipo , Ratas , Ratas WistarRESUMEN
It has been suggested that acetaldehyde has a biphasic effect on voluntary alcohol consumption. At low brain concentration, it might exert reinforcing effects, whereas high acetaldehyde levels would be predominantly aversive. The objective of the current study was to compare the effect of an intraperitoneal dose of acetaldehyde (50 mg/kg) in high-alcohol-drinking (UChB) and low-alcohol-drinking (UChA) rat lines, which differ in the activity of the brain mitochondrial class 2 aldehyde dehydrogenase (ALDH2) as a consequence of differences in their ALDH2 genotypes. A classical place-conditioning procedure was used to determine the reinforcing or aversive (or both) effects of acetaldehyde in ethanol-naive UChB and UChA rats. Environmental cues were paired with an intraperitoneal 50-mg/kg injection of acetaldehyde. On 10 consecutive days, each rat received one place conditioning per day; the acetaldehyde-pairing was alternated with saline-pairing. Results showed that conditioning with the 50-mg/kg dose of acetaldehyde induced place preference in UChB rats and place aversion in UChA rats. In a second experiment, UChB and UChA rats, pretested for ethanol preference, were injected with one 50-mg/kg dose of acetaldehyde or saline and tested for their voluntary ethanol consumption during 4 weeks. Results showed that the acetaldehyde dose induced a persistent and long-lasting enhancement of ethanol intake in UChB rats, but not in UChA rats. These results, together with the finding that after administration of a 50-mg/kg dose of acetaldehyde cerebral venous blood acetaldehyde levels in UChA rats were consistently higher than levels in UChB rats, support the suggestion that differential acetaldehyde levels, differential brain ALDH2 activity, or both were responsible for the different effects of acetaldehyde in the two rat lines.
Asunto(s)
Acetaldehído/farmacología , Consumo de Bebidas Alcohólicas/genética , Refuerzo en Psicología , Acetaldehído/sangre , Consumo de Bebidas Alcohólicas/sangre , Aldehído Deshidrogenasa/genética , Aldehído Deshidrogenasa Mitocondrial , Animales , Masculino , Ratas , Especificidad de la EspecieRESUMEN
We have previously found the existence of a relation between activity of the brain mitochondrial aldehyde dehydrogenase (ALDH2) and consumption of ethanol in rats of the low-alcohol-drinking (UChA) and the high-alcohol-drinking (UChB) strains. The aim of the present study was to determine whether UChA and UChB rats also differed in sensitivity to the aversive effects of acetaldehyde (AcH). Aversion to AcH was studied by using a conditioned taste aversion (CTA) paradigm. Ethanol naive UChA and UChB rats were administered AcH intraperitoneally (50, 100, or 150 mg/kg) or saline and exposed to a banana-flavored solution during five conditioning trials. A strong dose-dependent CTA to AcH was found in UChA rats, whereas UChB rats did not show a CTA to any dose of AcH. At equal doses of AcH, cerebral venous blood AcH levels in UChA rats were consistently higher than in UChB rats, a finding that may reflect the previously observed differences in the activity of ALDH2 between these strains. However, this observation is unlikely to explain fully the differences observed because aversion to AcH was developed in the UChA strain at blood levels of AcH that did not produce any aversion in the UChB strain. These results support the suggestion that, for the first time, differences in central or systemic effects of AcH per se may play a major role in determining the aversion to AcH in drinker and nondrinker animals.
Asunto(s)
Acetaldehído , Consumo de Bebidas Alcohólicas/fisiopatología , Reacción de Prevención , Condicionamiento Psicológico/efectos de los fármacos , Gusto , Acetaldehído/administración & dosificación , Acetaldehído/sangre , Acetaldehído/farmacología , Consumo de Bebidas Alcohólicas/sangre , Consumo de Bebidas Alcohólicas/genética , Animales , Encéfalo/irrigación sanguínea , Encéfalo/metabolismo , Condicionamiento Psicológico/fisiología , Relación Dosis-Respuesta a Droga , Femenino , Inyecciones Intraperitoneales , Ratas , Ratas Endogámicas , Especificidad de la Especie , Gusto/efectos de los fármacos , Gusto/fisiologíaRESUMEN
OBJECTIVE: To examine the efficacy of a combination of 4 blood markers of alcohol use in detecting alcohol-abusing pregnant women. STUDY DESIGN: Two new markers of alcohol use, whole blood-associated acetaldehyde and carbohydrate-deficient transferrin, and 2 traditional markers of alcohol use, gamma-glutamyl transpeptidase and mean red blood cell volume, were measured in the blood of pregnant women. Each woman was interviewed about alcohol and drug use, medical and obstetric histories, and nutrition. Each infant was examined by a clinician who was blinded to exposure status. RESULTS: All of the women who reported drinking an average of 1 or more ounces of absolute alcohol per day had at least 1 positive blood marker. The infants of mothers with 2 or more positive markers had significantly smaller birth weights, lengths, and head circumferences than the infants with negative maternal screens. The presence of 2 or more positive markers was more predictive of infant outcome than any self-reporting measure. CONCLUSIONS: These markers, which detect more at-risk pregnant women than self-reporting methods, could lead to better efforts at detection and prevention of alcohol-induced fetal damage.
Asunto(s)
Consumo de Bebidas Alcohólicas/efectos adversos , Etanol/envenenamiento , Trastornos del Espectro Alcohólico Fetal/diagnóstico , Embarazo/sangre , Diagnóstico Prenatal , Efectos Tardíos de la Exposición Prenatal , Acetaldehído/sangre , Adulto , Biomarcadores/sangre , Peso al Nacer , Estatura , Índices de Eritrocitos , Etanol/efectos adversos , Femenino , Trastornos del Espectro Alcohólico Fetal/prevención & control , Cabeza/anatomía & histología , Humanos , Recién Nacido , Anamnesis , Fenómenos Fisiológicos de la Nutrición , Valor Predictivo de las Pruebas , Resultado del Embarazo , Historia Reproductiva , Método Simple Ciego , Trastornos Relacionados con Sustancias/sangre , Transferrina/análisis , gamma-Glutamiltransferasa/sangreRESUMEN
Acetaldehyde, a product of alcohol metabolism, is known to bind covalently to plasma and red cell proteins, yielding stable adducts which have recently shown are recognized as foreign by the immune system. The present study demonstrates that immunization of mice with protein-acetaldehyde adducts in aluminum hydroxide gel results in the production of reaginic antibodies that recognize the adducts and trigger an allergic-anaphylactic reaction. These findings may lead to new approaches in the treatment of excessive alcohol consumption in humans.
Asunto(s)
Acetaldehído/efectos adversos , Hipersensibilidad a las Drogas/etiología , Inmunización , Acetaldehído/sangre , Acetaldehído/inmunología , Alcoholismo/terapia , Aldehído Deshidrogenasa/antagonistas & inhibidores , Animales , Cianamida/farmacología , Disulfiram/farmacología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , RatasAsunto(s)
Ratones , Animales , Humanos , Acetaldehído/efectos adversos , Hipersensibilidad a las Drogas , Inmunización , Acetaldehído/sangre , Acetaldehído/inmunología , Alcoholismo/terapia , Aldehído Deshidrogenasa/antagonistas & inhibidores , Cianamida/farmacología , Disulfiram/farmacología , Ratones Endogámicos C57BLRESUMEN
Estudamos os efeitos da ingestäo aguda de bebidas alcoólicas sob o ponto de vista clínico, eletrocardiográfico e laboratorial, em 23 indivíduos, 16 sadios e 7 com antecedentes de cardiopatia, que näo faziam uso habitual de álcool. Todos apresentaram, após a ingestäo alcoólica, aumento significativo das taxas sangüíneas de álcool e acetaldeído. Os níveis séricos de potássio, magnésio e glicose näo sofreram variaçöes importantes, o mesmo ocorrendo com a duraçäo das ondas P e dos intervalos PR, com a morfologia das ondas P e dos complexos QRS, com o eixo elétrico de P e de QRS e com as ondas U. Observamos, em todos os casos, queda da pressäo arterial sistólica, após a ingestäo alcoólica. O grupo de indivíduos com antecedentes de cardiopatia apresentou algumas alteraçöes significativas, caracterizadas por: aumentos da taxa sangüínea de cálcio e de transaminase glutamooxalacética; queda da pressäo arterial diastólica e aumento da freqüência cardíaca; arritmias cardíacas (arritmia sinusal e extra-sistoles ventriculares); diminuiçäo da amplitude dos complexos QRS; aumento do intervalo QT, alteraçöes da repolarizaçäo elétrica ventricular, com aparecimento de ondas T bífidas, invertidas e de baixa voltagem. Esses resultados sugerem que alteraçöes significativas da performance cardíaca conseqüentes à ingestäo alcoólica, ocorreram apenas em indivíduos já portadores de distúrbios cardiovasculares