Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278080 (physical dependence)
 1,658 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The microsomal cytochromes P-450 and b5 and the enzymes of the hepatic microsomal electron transport system (HMETS) including NADPH-cytochrome c reductase and NADPH oxidase activities were monitored in male ICR mice (25-30 g) over a six-day period following the repeated oral administration of 7, 14 and 28 mg/kg per day of l-alpha-acetylmethadol hydrochloride (LAAM) or an equivalent volume of water. Cytochrome P-450 and the microsomal enzyme activity of NADPH oxidase were maximally elevated (three- to four-fold above control values) by the third day of LAAM administration (28 mg/kg per day). These elevations not only correlated on a dose and a temporal basis with previously reported microsomal activities including LAAM N-demethylase, but also with the reported development of cellular tolerance and physical dependence following an identical regimen of LAAM. In addition, NADPH-cytochrome c reductase and cytochrome b5 increased in activity and content, respectively, after the repeated administration of this narcotic. However, the enzyme activity was first significantly elevated after only a single dose of LAAM. Thereafter, it showed a pattern of induction similar to that of NADPH oxidase. In contrast, cytochrome b5 was only elevated after the last repeated dose. The significance of these findings is discussed in some detail relative to the generation of the two analgesically active metabolites of LAAM.
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PMID:Additional metabolic correlates of 1-alpha-acetylmethadol (LAAM)-induced cellular tolerance and physical dependence: the role of the hepatic microsomal electron transport system. 11 96

Following the repeated oral administration of l-alpha-acetylmethadol (LAAM) employing a dose (28 mg/kg per day) shown to induce its own metabolism by three- to four-fold, mice exhibited a rapid development of cellular tolerance and physical dependence which correlated on a temporal basis with this self-induction of LAAM metabolism. Evidence of cellular tolerance included significant elevations in the LAAM oral LD50, LAAM ICV (intracerebroventricular) LD50, LAAM oral AD50 and the LAAM ICV AD50 following repeated administration of this narcotic. Since the ICV parameters and the morphine AD50 were elevated over water control values, cellular tolerance appeared to play an important role in explaining the elevations noted for the oral parameters because the former were not influenced by changes in the rate of LAAM metabolism. Moreover, SKF-525A, a microsomal enzyme inhibitor, had little effect on the LAAM oral LD50 and the LAAM oral AD50, further indicating a minor role for dispositional tolerance. It is concluded that the induction noted for repeated oral LAAM administration most likely is responsible for generating more potent metabolites which in turn act to produce the cellular tolerance and physical dependence in these mice through constant exposure of the CNS.
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PMID:Development of cellular tolerance to lethality and analgesia concurrent with physical dependence following repeated oral administration of LAAM. 57 49

This study reproduces in experimental animals the sequential development of all the liver lesions seen in the human alcoholic: in 15 baboons fed ethanol, all developed fatty liver, five progressed to hepatitis, and five had cirrhosis. Maintenance of a nutritionally adequate regimen despite the intake of inebriating amounts of ethanol (50% of total calories) was achieved by incorporation of the ethanol in a totally liquid diet. Upon ethanol withdrawal, signs of physical dependence, such as seizures and tremors, developed. Ultrastructural changes of the mitochondria and the endoplasmic reticulum were already present at the fatty liver stage and persisted throughout the hepatitis and cirrhosis. The lesions were similar to those observed in alcoholics (including the inflammation and the central sclerosis) and differed from the alterations produced by choline and protein defiencies. At the fatty liver stage, some "adaptive" increases in activity of microsomal enzymes [aniline hydroxylase (EC 1.14.14.1) and the microsomal ethanol oxidizing system] were observed, but these tended to disappear with the development of hepatitis and cirrhosis. Fat accumulation was also much more pronounced in the animals with the hepatitis as compared with those with simple fatty liver (an 18-fold compared with 3- to 4-fold increase in liver triglycerides). The demonstration that these lesions can develop despite an adequate diet indicates that in addition to correction of the nutritional status, control of alcohol intake is mandatory for the management of patients with alcoholic liver injury.
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PMID:Sequential production of fatty liver, hepatitis, and cirrhosis in sub-human primates fed ethanol with adequate diets. 105 27

Lipoperoxidation, a degradative process of membranous polyunsaturated fatty acids, has been suggested to represent an important mechanism in the pathogenesis of ethanol toxicity on the liver and possibly also on the brain. Catalysis by transition metals, especially iron, is involved in the biosynthesis of free radicals contributing to lipid peroxidation. Although the exact nature of the redox-active iron implicated in this catalysis is still unknown, it has been well established that lipid peroxidation can be prevented in vitro by iron chelators such as desferrioxamine. Deprivation of redox-active iron through desferrioxamine inhibits by about 50% the microsomal oxidation of ethanol in vitro and reduces very significantly in vivo the overall ethanol elimination rate in rats. Administration of desferrioxamine together with ethanol also reduces the ethanol-induced disturbances in the antioxidant defense mechanisms of the hepatocyte. It also reduces in mice both the severity of physical dependence on ethanol and lethality following the acute administration of a narcotic dose of ethanol. Chronic overloading of rats with iron results, on the opposite, in an increased rate of ethanol elimination, although alcohol dehydrogenase and catalase activities are reduced and cytochrome P-450 depleted in the liver of such iron-overloaded animals. The magnitude of the ethanol-induced increase in lipid peroxidation and decrease in the major membranous antioxidant, alpha-tocopherol, is exacerbated in iron-overloaded rats. Several disturbances of iron metabolism have been reported in human alcoholics. Their contribution to ethanol toxicity appears very likely in the case of hepatic siderosis associated with alcohol abuse. Ethanol could however disturb iron metabolism even in the absence of gross abnormalities of the total iron stores. It is suggested that ethanol intoxication could increase cellular redox-active iron, thus contributing to an enhanced steady-state concentration of reactive-free radicals. This oxidative stress would lead to lipoperoxidative damage and cellular injury.
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PMID:Involvement of iron and iron-catalyzed free radical production in ethanol metabolism and toxicity. 303 5

This study was designed to assess the strain differences in pentobarbital toxicity, narcosis, the development of tolerance and physical dependence, the half-life of pentobarbital and the activities of hepatic microsomal electron transfer chain in DBA/2J, C57BL/6J and ICR mice. The comparisons of responses to acute pentobarbital-induced narcosis with two different doses revealed that DBA was most sensitive among these strains. When continuous administration of pentobarbital by pentobarbital pellet implantation is concerned, four criteria were used to assess strain differences: 1) determination of the duration of the loss of righting reflex during pentobarbital pellet implantation; 2) cumulative mortality after pentobarbital pellet implantation; 3) degree of tolerance development after 3 days of s.c. implantation of a 75-mg pentobarbital pellet by the relative decrease in the pentobarbital sleeping time; and 4) assessment of hyperexcitability by pentylenetetrazol- and audiogenic-induced seizures after pellet removal. The order of susceptibility to continuous pentobarbital pellet implantation was found to be as follows: DBA/2J > C57BL/6J > ICR. The biochemical data also revealed that the half-life of pentobarbital in DBA/2J mice was significantly longer than that of C57BL/6J or ICR mice in both brain and serum. Further studies also showed that DBA/2J mice have lower hepatic cytochrome P-450 and cytochrome b5 levels and NADPH dehydrogenase and NADPH-cytochrome c reductase activities as compared with the other strains of mice. However, these parameters were markedly induced in DBA/2J mice after the development of tolerance to pentobarbital. It appears that the differences in genetic variation could be of importance for further studies in gaining insight of the mechanism of barbiturate tolerance and dependence.
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PMID:Pharmacological responses to pentobarbital in different strains of mice. 719 35

Mice were continuously administered with barbital by the sc implantation of 16 mg barbital pellet (acid form). Serum and brain barbital levels were assessed at different times after pellet implantation. After 3 days of implantation the barbital pellet was removed and the mice were observed for a 96 hr period. A 30% decrease in sleeping time was observed 72 hr after pellet removal when mice were challenged with 400 mg/kg of barbital ip. Brain and serum barbital levels upon awakening were also assessed with a dose of sodium barbital, 400 mg/kg ip, administered 72 hr after removal of either a barbital or placebo pellet. It was observed that serum and brain barbital concentrations were significantly higher in barbital treated animals than in controls. The effect of barbital pellet implantation on pentobarbital (75 mg/kg, ip) sleeping times was also assessed. Cross tolerance to pentobarbital was observed 24, 48, and 72 hr after barbital pellet implantation. The results demonstrated that barbital pellet implantation enhanced hepatic drug metabolism as evidenced by significant increases in hepatic microsomal N-demethylase and hydroxylase activities. CNS hyperexcitability, an indication of dependence, was assessed by the method of pentylenetetrazol (PTZ) induced convulsions (60 mg/kg, sc). At 48 and 72 hr after pellet removal, PTZ induced convulsions increased by 41% and 35%, respectively, over control values. Index of dependence was also substantiated by a decrease in threshold for electroshock. These studies substantiate the validity of this experimental model for the assessment of the development of tolerance to and physical dependence on barbiturates.
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PMID:Continuous administration of barbital by pellet implantation. 719 83