摘要:

Evidence from animal models and from recent reports on the efficacy of the opioid antagonist naltrexone in the treatment of alcoholism suggests that the endogenous opioid systems may play a role in alcohol seeking behavior. The gene encoding preproenkephalin A(PENK)is flanked at its 3’end by a polymorphic (CA)n. repeat. We determined the allele frequencies for this locus in samples of Chinese and Atayal living in Taiwan, Caucasians living in the United States and Byelorussia, and African‐Americans living in the United States. We compared the allele frequencies of nonalcoholics in each population with those of alcoholics with or without alcohol‐induced organ pathology. There was no difference in allele frequencies within any racial group when alcoholics with or without organ pathology were compared; there was also no difference in allele frequency between nonalcoholics and alcoholics within the two Asian populations, Caucasians, or African‐Americans. There were highly significant differences in the frequency of the various length polymorphism between the Asian, Caucasian, and African‐America

ISSN:0145-6008    

DOI:10.1111/j.1530-0277.1994.tb00905.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Protein accumulation in liver cells contributes to alcohol‐induced hepatomegaly and is the result of an ethanol‐elicited deceleration of protein catabolism (Alcohol Clin Exp Res 1349, 1989). Because lysosomes are active in the degradation of most hepatic proteins, the present studies were conducted to determine whether ethanol administration altered the proteolytic activities of partially purified hepatic lysosomes. Rats were fed liquid diets containing either ethanol (36% of calories) or isocaloric maltodextrin for periods of 2–34 days. Prior to death, all animals were injected with [3H]leucine to label hepatic proteins. Rats subjected to even brief periods of ethanol feeding (2–8 days) exhibited significant hepatomegaly and hepatic protein accumulation compared with pair‐fed control animals. Crude liver homogenates and isolated lysosomal‐mitochondrial and cytosolic subfractions were incubated at 37°C, and the acid‐soluble radioactivity generated during incubation was measured as an index of proteolysis. At neutral pH, in vitro protein breakdown in incubated liver homogenates and subcellular fractions from control and ethanol‐fed rats did not differ significantly. The extent of protein hydrolysis increased when samples were incubated at pH 5.5, which approximates the pH optimum for catalysis by lysosomal acid proteases. Under the latter conditions, partially purified lysosomes from control animals had 2‐fold higher levels of proteolysis than corresponding fractions from ethanol‐fed rats. The difference in proteolytic capacity appeared to be related to a lower latency and a higher degree of fragility of lysosomes from ethanol‐fed rats at the acidic pH. The results suggest that ethanol‐induced alterations in lysosomal membranes may be partially responsible for their altered capacities for protein hydrolysis. Such changes may result from ethanol‐related alterations in lipid metabolism that may affect lysosome biogenesis or the maturation of lysosome

ISSN:0145-6008    

DOI:10.1111/j.1530-0277.1994.tb00906.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Withdrawal Seizure‐Prone (WSP) and ‐Resistant (WSR) mice have been bidirectionally selected for severity of handling‐induced convulsions (HIC) following withdrawal from 72 hr of chronic ethanol vapor inhalation. During selection, daily injections of the alcohol dehydrogenase inhibitor, pyrazole, were used to enhance and stabilize blood ethanol concentrations (BEC). After 26 generations of selection, WSR mice show lower withdrawal BEC than WSP mice exposed to the same ethanol vapor concentrations. Because it is desirable to compare mice maintained at the same BEC to assess correlated responses to selection, this has necessitated exposing WSR mice to higher ethanol vapor concentrations than WSP mice to achieve matched chronic BEC. The experiments reported herein demonstrate two methods for producing matched withdrawal BEC: (1) by exposing mice to the same ethanol vapor concentration and varying the pyrazole dose; and (2) by administering only ethanol at different vapor concentrations and selecting some mice with approximately the same BEC. When exposed to the same ethanol vapor concentration, WSR mice given 1.0 mmol/kg pyrazole had withdrawal BEC equivalent to WSP mice given 0.75 mmol/kg pyrazole. However, WSP mice had much more severe withdrawal HIC than WSR mice. WSP and WSR mice metabolized ethanol at the same rate following withdrawal. The basis for the differential effectiveness of pyrazole is unknown. We also exposed mice to higher ethanol vapor concentrations in the absence of pyrazole. By exposing WSR mice to higher concentrations than WSP, roughly equivalent BEC on withdrawal was achieved. Because BEC are more variable in the absence of pyrazole, it was necessary to select animals of each genotype to achieve relatively matched BEC. Again, WSP mice had much more severe HIC on withdrawal tha

ISSN:0145-6008    

DOI:10.1111/j.1530-0277.1994.tb00907.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Retinoic acid (RA), a metabolic product of vitamin A, has been shown to affect a variety of immune functions, including monocytes. Monocyte functions and mediator production are also modulated by ethanol exposure. This study demonstrates that therapeutic doses of RA (0.1–10 μM) significantly increase transforming growth factor‐β(TGFβ) production both in THP‐1, human myelomonocytic cells, and in human peripheral blood monocytes. We have previously reported TGFB induction by ethanol in human Mø.Combination of RA stimulation with acute in vitro ethanol treatment, however, resulted in significantly lower Mø TGFβ production than TGFB levels induced by RA alone (p<0.003). Down‐regulation of MøTGFβ production by ethanol was tested at the concentration range of 25–150 mM and occurred both at high and low RA concentrations (10–0.1μM). In contrast to its inhibitory effect on RA‐induced MøTGFβ production, ethanol augmented TGFB production induced by mura‐my1 dipeptide (20 μg/ml), suggesting that ethanol can either up‐ or down‐regulate Mø TGFB production, depending on the costimulatory factors. RA also induced a moderate increase in Mø tumor necrosis factor‐α (TNFα) production, which was down‐regulated by ethanol both at the level of secreted and cell‐associated TNFα. In addition to regulation of cytokine production, both RA and ethanol decreased expression of CD4 on THP‐1 cells. The degree of inhibition of CD4 expression by RA was more significant than by ethanol, but RA‐induced decrease in CD4 expression was not significantly affected by the combined stimulation with ethanol. These results provide further evidence for the immunoregulatory potential of nutritional and dietary factors, such as RA and ethan

ISSN:0145-6008    

DOI:10.1111/j.1530-0277.1994.tb00908.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Naive, male rats (n= 14) were given continuous access to 10% alcohol and water for a period of 6 weeks. Concurrent taste reactivity tests showed a consistent increase in ingestive responding to a range of alcohol concentrations (100%‐40%) over the course of alcohol access. The rats also showed a consistent decrease in aversive responding over time. These data suggested that the palatability of alcohol increased with alcohol experience. After a 1‐month period of alcohol abstinence, however, ingestive taste reactivity to alcohol returned to the same level as that found when the rats were alcohol naive, whereas aversive responding approached the level seen initially. A separate control group (n= 13) given only water for the same length of time failed to show similar changes in taste reactivity to alcohol soluti

ISSN:0145-6008    

DOI:10.1111/j.1530-0277.1994.tb00909.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Chronic ethanol consumption produces nutrient malabsorption. The mechanisms by which this occurs are poorly understood. One potential mechanism is an alteration in microvillus membrane (MVM) composition and fluidity. The effects of in vivo ethanol exposure on MVM lipid composition and fluidity were determined in rats fed either a standard diet or 15% ethanol in water for 2 months. Acute jejunal exposure to 4% ethanol was also performed in vivo in each feeding group. Acute exposure to ethanol produced an increase in static and dynamic membrane fluidity associated with a decrease in MVM cholesterol regardless of prior ethanol exposure. Chronic ethanol feeding alone did not alter membrane fluidity. Changes in membrane fatty acid composition were minor and variable after both acute and chronic ethanol exposure. Prior chronic ethanol feeding did not prevent the acute effects of ethanol on MVM composition or fluidity. These data support the theory that ethanol acutely disrupts nutrient transport by changing MVM lipid fluidity. The absence of adaptive changes in membrane composition and fluidity may also explain the persistent absorptive defects seen with chronic alcoholism.

ISSN:0145-6008    

DOI:10.1111/j.1530-0277.1994.tb00910.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

The anococcygeus muscle of the rat is innervated by both excitatory adrenergic and inhibitory nonadrenergic, noncholinergic (NANC) neurons. The transmitter released from NANC neurons appears to be nitric oxide or a related molecule. In vitro, acute administration of ethanol inhibited, in a dose‐dependent manner, NANC‐induced relaxation of anococcygeus muscle obtained from ethanol‐naive animals. Two days of in vivo ethanol administration resulted in an increase in the maximal relaxation induced by stimulation of NANC neurons and in a significant shift to the right of the acute ethanol dose‐response curve for inhibition of NANC relaxation. The sensitivity of the anococcygeus muscle to relaxation induced by the nitric oxide donors, acidified sodium nitrite or sodium nitroprusside, was not altered significantly by acute in vitro or chronic ethanol treatment 2 days in vivo. These data suggest that acutely administered in vitro ethanol inhibits the production of nitric oxide induced by stimulation of NANC neurons. Data further suggest that 2 days of ethanol administration in vivo produce an enhanced responsiveness of the NANC neurons to transmural stimulation and that this enhanced responsiveness accounts for the tolerance to the inhibition induced by the acutely administered ethanol i

ISSN:0145-6008    

DOI:10.1111/j.1530-0277.1994.tb00911.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Our previous study indicated that 5‐hydroxytryptamine (5‐HT) immunoreactive fiber densities were decreased in specific areas of the brain in alcohol‐preferring rats (P) when compared with alcohol‐nonpreferring rats (NP). The results of our current study show that there are quantitative and qualitative differences in 5‐HT innervation in other selected regions of the forebrains of P rats. The 5‐HT fiber density in the brains of young adult P and NP rats was measured by immunocytochemistry and quantitative image analysis. A routine error of two‐dimensional quantitation of nerve fiber was addressed and an adjustment was made. The amount of 5‐HT fibers was significantly lower in CA4 and fasciola cinereum of the dorsal hippocampus, caudate‐putamen, and hypothalamus of the P as compared with NP rats (unpaired Student's t tests).In examining the fiber types, we found that, in the frontal cortical and hippocampal regions, where normally fine 5‐HT fibers with small varicosities and thick 5‐HT fibers with large varicosities coexist, fewer fine 5‐HT fibers were seen in P rats as compared with NP rats the fine fibers are known to be vulnerable to abusive drugs. These observations indicate that (a) there are quantitative differences in 5‐HT innervation or that the 5‐HT in some 5‐HT fibers is reduced to a level undetectable by immunocytochemistry, and (b) the fine 5‐HT fibers are specifically reduced to a greater degree in the selected brain regions of P rats when compared with that of NP rats. The involvement of the 5‐HT system

ISSN:0145-6008    

DOI:10.1111/j.1530-0277.1994.tb00912.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Phospholipase D has been shown to be a key enzyme in the signal transduction systems involved in neutrophil activation. In the presence of ethanol, the enzyme catalyzes a transphosphatidylation reaction through which phosphatidylethanol is formed instead of the normal product phosphatidic acid. The effects of ethanol on the formation of phosphatidylethanol and phosphatidic acid was studied in neutrophils from human alcoholics in vitro. Neutrophils were isolated and cellular lipids were labeled with [3H]oleate, whereafter the cells were preincubated with cytochalasin B. Subsequently, cells were stimulated with the chemotactic peptide formyl‐Met‐Leu‐Phe in the presence of ethanol concentrations ranging from 0 to 200 MM. In the presence of ethanol, both neutrophils from alcoholics and controls produced phosphatidylethanol, with a concomitant reduction of the production of phosphatidic acid. The amounts of phosphatidylethanol and phosphatidic acid formed were dependent on the concentration of ethanol. In neutrophils from alcoholics, a higher apparent Kmfor the phospholipase D‐mediated transphosphatidylation reaction was noted (58 MM ethanol compared with 28 mM in controls). The in vivo mass of phosphatidylethanol in recently drinking alcoholics was also analyzed in neutrophils. Measurable phosphatidylethanol levels (average 5.6 pmol/106neutrophils) were found in alcoholics up to 23 hr after the last intake of ethanol. Thus, in addition to the ethanol‐induced changes in the normal production of phosphatidic acid, phosphatidylethanol accumulated in vivo in alcoholics may be expected to influence neutrophil

ISSN:0145-6008    

DOI:10.1111/j.1530-0277.1994.tb00913.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Mammalian alcohol dehydrogenase (ADH) is thought to be involved in the reversible oxidation of vitamin A or retinol to retinal for retinoic acid synthesis. Retinoic acid is a potent transcriptional regulator and a morphogen. It was proposed that the competition of consumed ethanol with retinol oxidation by ADH might explain developmental disorders seen with fetal alcohol syndrome. We report herein the dative efficiency (V/Km) of eight human ADH isoenzymes for oxidation of all‐trans‐retinol and reduction of three retinal isomers (all‐frans, Scis, and 134s‐retinal). Class IV σσ and class II ππ isoenzymes are the most efficient forms, with VIKmvalues ∼100 and 30 times greater, respectively, than class I β1β1or γ1,γ1. σσ exhibits the highest V/K, (1–2 μm−1min‐−1), followed by ππ, with V/Kmof 0.5–0.6 pm−1min−1for all‐trans‐retinol, all‐trans‐retinal, and 9‐cis‐retinal. ππ also has the lowest Km(11–14 μm) for all‐trans‐retinol and three retinal isomers. αα shows an intermediate efficiency, with V/Kmof 0.09–0.2 am−1min−1and a relatively low Kmof 16–24 μm for all four substrates. αα has the highest efficiency of all tested isoenzymes for 13‐cis‐retinal. Class 111 xx is inactive with all the tested retinoids. The contribution of class IV σσ, class II ππ, and even class I αα to retinol oxidation and retinal reduction in vivo will depend on expression of these isoenzymes in specific tissues, relative activities toward free retinol/retinal versus that bound to the cellular retinol bindin

ISSN:0145-6008    

DOI:10.1111/j.1530-0277.1994.tb00914.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY