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Biomedical subjects

A D Thomson

Publications and source records attributed to A D Thomson.

At least 37 records · Page 2Linked to original sources
PubMed1986

Inhibition of ethanol induced hepatic vitamin A depletion by administration of N,N'-diphenyl-p-phenylene-diamine (DPPD).

The administration of ethanol as 36% of the total calories in a nutritionally adequate liquid diet for three weeks to male Wistar rats caused a 36% decrease in hepatic vitamin A levels (P less than 0.001) when compared with glucose pair-fed control rats, without affecting serum levels of the vitamin. Simultaneous administration of a synthetic antioxidant, DPPD (N,N'-diphenyl-p-phenylene-diamine) to ethanol-fed rats caused a 73% decrease in the extent of the ethanol induced hepatic vitamin A depletion (P less than 0.001). DPPD administration did not affect weight gain, dietary (and hence ethanol) intake or serum ethanol and vitamin A levels in ethanol-fed rats, nor did it affect hepatic or serum vitamin A levels in pair-fed controls. Increased hepatic catabolism of retinoic acid due to induction of cytochrome P450 by ethanol has been suggested as a mechanism of depletion. In the current study, DPPD administration to ethanol-fed rats did not reverse the ethanol induced increase in microsomal cytochrome P450 concentrations or aniline hydroxylase activity. These findings indicate that the ethanol induced hepatic vitamin A depletion can be largely dissociated from the induction of cytochrome P450. In view of the potent free radical scavenging activity of vitamin A, and the protective effect of DPPD against ethanol induced hepatic loss of the vitamin, this study suggests that increased free radical generation and direct peroxidation of vitamin A may be an important mechanism by which ethanol induced hepatic vitamin A depletion occurs in the rat.

Alcoholism↗
PubMed1986

Reduced stability of rat brain transketolase after conversion to the apo form.

The stability of rat brain transketolase, whether measured at 37 or 0 degree C, was reduced after conversion to the apo form by removal of thiamine diphosphate, as shown by a decline in the activity recovered when assayed in the presence of thiamine diphosphate. Both the shape of the breakdown curve and the failure to recover the full activity, even after incubation with thiamine diphosphate, showed that the breakdown of the apotransketolase was complex. The initial rate of breakdown of the apoenzyme was sharply pH dependent, being minimal at 37 degrees C at a pH value of 7.6, close to that likely to exist in vivo. The rate rose sharply with deviation of the pH in either direction. The stability of the enzyme on storage at 0 degree C showed a similar pattern of pH dependence, provided that allowance is made for temperature effects on dissociation constants. These findings provide further support for the hypothesis that differences in brain transketolase may play a part in the etiology of Wernicke-Korsakoff's syndrome.

Animals↗
PubMed1985

The effect of methylene blue on the hepatocellular redox state and liver lipid content during chronic ethanol feeding in the rat.

Feeding of ethanol in a liquid diet to male Wistar rats caused decreases in the hepatic cytosolic and mitochondrial [NAD+]/[NADH] ratios. This redox-state change was attenuated after 16 days of feeding ethanol as 36% of the total energy intake. Supplementation of the ethanol-containing liquid diet with Methylene Blue largely prevented the ethanol-induced redox state changes, but did not significantly decrease the severity of the hepatic lipid accumulation that resulted from ethanol ingestion. Methylene Blue did not affect body-weight gain, ethanol intake or serum ethanol concentrations in ethanol-fed rats, nor did the compound influence the hepatic redox state or liver lipid content of appropriate pair-fed control animals. These findings suggest that the altered hepatic redox state that results from ethanol oxidation is not primarily responsible for the production of fatty liver after long-term ethanol feeding in the rat.

Animals↗
PubMed1985

The roles of the hepatocellular redox state and the hepatic acetaldehyde concentration in determining the ethanol elimination rate in fasted rats.

Ethanol administration (2 g/kg i.p.) to fasted male Wistar rats caused, on average, a 64% decrease in the cytosolic free NAD+:NADH ratio and a 41% decrease in the mitochondrial free NAD+:NADH ratio measured 90 min after ethanol was injected. Treatment of animals with either Naloxone (2 mg/kg i.p.) 1 hr after ethanol or 3-palmitoyl-(+)-catechin (100 mg/kg p.o. 1 hr before ethanol) prevented these ethanol induced redox state changes, without affecting the ethanol elimination rate or the hepatic acetaldehyde concentration measured at 90 min after ethanol administration. The thiol compounds cysteine and malotilate (diisopropyl-1,3-dithiol-2-ylidene malonic acid) significantly lowered the hepatic acetaldehyde concentrations measured at 0.75, 1.5 and 6.0 hr after ethanol, and caused a 29% and 12% increase respectively in the ethanol elimination rate, without affecting the ethanol induced alterations in the NAD+:NADH ratio. Pretreatment of animals with the aldehyde dehydrogenase inhibitor, cyanamide (1 mg/kg or 15 mg/kg p.o. one hour before ethanol), caused increases of up to 23-fold in the hepatic acetaldehyde level, without influencing the cytosolic NAD+:NADH ratio in ethanol dosed rats, while significantly reducing the ethanol elimination rate by up to 44%, compared with controls. These results suggest that ethanol oxidation by cytosolic alcohol dehydrogenase may be regulated in part by the hepatic acetaldehyde concentration achieved during ethanol metabolism rather than NADH reoxidation, either to supply NAD for the dehydrogenase, or to reduce inhibition of the enzyme by NADH, being a rate-limiting factor in ethanol metabolism in fasted rats.

Acetaldehyde↗
PubMed1985

Transketolase variant enzymes and brain damage.

Human red blood cell transketolase has been resolved into two components by gel filtration. One component has its thiamine diphosphate coenzyme firmly bound whilst the other variant of the enzyme is a smaller molecule which is inactive without added thiamine diphosphate, for which it has a reduced affinity. It is concluded that the failure to detect an increase in activation in the commonly used clinical test of red cell transketolase activation by raising the thiamine diphosphate concentration above about 0.3 mmol/l is likely to be due to masking of the effect of activation of the low affinity variant in haemolysates from normal red blood cells by the inhibitory effect of excess thiamine diphosphate upon the activity of the high affinity form of the enzyme with which it is mixed. Increased activation by higher thiamine diphosphate concentrations is sometimes seen in haemolysates from the blood of chronic alcoholics, as well as in the low molecular weight fraction separated from normal haemolysates. It is considered likely that there are at least two variants of the enzyme and that the low molecular weight variant represents a damaged form of the enzyme normally present in small amounts but formed in larger proportions in vivo in abnormal conditions like chronic alcoholism and thiamine deficiency as well as by enzyme breakdown in vitro. In the light of these conclusions some recently proposed hypotheses regarding the role of transketolase in the genesis of brain damage in thiamine deficiency are reconsidered and a modified mechanism is proposed consistent with these and other recent findings.

Adult↗
PubMed1985

Alcoholic malnutrition and the small intestine.

Malnutrition is common in chronic alcoholics, although its severity may depend on the social characteristics of the patient group under study and their severity of alcohol dependence. General malnutrition is often reflected in body weight loss, mainly of adipose and muscle tissue. This loss of nutritional reserves is partly due to inadequate protein intake in the face of continued alcohol ingestion. However, there is also evidence that ethanol is relatively ineffective as a source of calories, in spite of its high theoretical calorific value. An increased metabolic rate and tissue oxygen consumption following alcohol ingestion, without parallel increases in phosphate bond energy production or anabolic processes demonstrate the poor value of ethanol as an alternative calorie source to carbohydrate, fat or protein. This situation of nutritional imbalance is often compounded in chronic alcoholics by the effects that ethanol has on gastrointestinal function. These include increased mucosal permeability which may lead to 'leakage' of nutrients from the blood to the gut lumen, increased gut motility with increased transit times, and impaired salt and water absorption. Alcohol inhibits absorption of vitamins and nutrients by active transport processes, an effect that may be crucial in precipitating specific nutrient deficiencies (e.g. thiamine) in the alcoholic, in addition to the role of reduced dietary intake of vitamins and minerals in alcoholics that also contributes to such deficiency states. The end result may be severe functional impairment and tissue damage in other organs, notably the liver and the brain, as a consequence of specific vitamin and nutrient deficiencies arising in chronic alcoholics by these mechanisms.

Adenosine Triphosphate↗
PubMed1985

The effect of naloxone on the hepatocellular redox state and serum ethanol concentrations following acute ethanol administration.

Naloxone hydrochloride (2.0 mg/kg) has been found to reverse the significant decreases in the hepatic cytosolic and mitochondrial [NAD+]/[NADH] ratios observed after acute ethanol administration in rats. This correction of the ethanol-induced changes in the hepatocellular redox state by naloxone was, however, not associated with any lowering of serum ethanol concentrations or an observable reduction in the extent of intoxication. This lack of antagonism of alcohol intoxication by naloxone was not affected by the feeding status of the animals, the time point after naloxone administration at which serum ethanol concentration was determined or the method used for ethanol analysis. Thus this study has failed to confirm that naloxone antagonises acute alcohol intoxication, in spite of its potent ability to reverse the ethanol-induced changes in the hepatic redox state.

Alcoholic Intoxication↗
PubMed1984

Alloxan-induced diabetes in the rat - protective action of (-) epicatechin?

Administration of alloxan (150 mg/kg body weight, i.p.) to male Wistar rats induced a reproducible and persistent diabetes mellitus as evidenced by elevated serum glucose and low serum insulin concentrations. Administration of either (-)epicatechin or (+)catechin (250 mg/kg, i.p. on each occasion) at 36, 24, 12 and 1 hour before and at 12 and 24 hours after alloxan administration did not prevent the induction of the diabetes. Similarly, treatment of animals with (-)epicatechin or (+)catechin (125 mg/kg i.p. twice daily) for 21 days commencing 24 hours after alloxan administration did not reverse the persisting elevated serum glucose and low serum insulin concentrations. Moreover, administration of these compounds did not relieve any of the symptoms of the alloxan-induced diabetes such as poor weight gain, polyuria or polydipsia. Thus, this study does not confirm previous reports of prophylactic and curative effects of (-)epicatechin against alloxan-induced diabetes in rats, in spite of the high dosages of the compounds used in these experiments.

Animals↗
PubMed1984

(+)-Cyanidanol-3 for alcoholic liver disease: results of a six-month clinical trial.

A prospective randomized double-blind trial of (+)-cyanidanol-3 at a dose of 2 g daily (500 mg qds) for six months versus placebo has failed to demonstrate statistically significant clinical, biochemical or histological benefit in patients with biopsy-proven alcoholic liver disease although certain trends were identified. The group receiving the active drug tended to drink more both before and during the trial and had mean serum aspartate aminotransferase (AsT) and gamma-glutamyltranspeptidase (gamma-GT) levels which were higher on admission to the trial. After the fourth week of treatment, the mean serum levels of these enzymes remained consistently lower in the group receiving the active drug. In order to reproduce the beneficial effects of the drug observed in the rat, it is suggested that further trials be conducted with the dosage so far used in man (ca. 20-40 mg/kg daily) increased toward that successfully employed in animal experiments (200 mg/kg daily).

Alcohol Drinking↗
PubMed1984

Nutrition and vitamins in alcoholism.

Chronic alcoholics frequently have evidence of nutritional deficiency due to decreased intake, reduced uptake and impaired utilisation of nutrients. The alcoholic has increased nutrient requirements due to greater metabolic demands and the need for tissue repair. Chronic alcohol-related brain damage can often be a direct result of nutrient depletion, particularly of the vitamins thiamine, B12, nicotinamide and pyridoxine. Lesser degrees of brain damage are frequently unrecognised, and by the time a vitamin deficiency syndrome has developed and been diagnosed, irreversible damage has often occurred. The development of suitable computerised psychometric tests may allow earlier detection of brain malfunction associated with malnutrition, which can be reversed by nutrient repletion before permanent damage occurs. Circulating levels of vitamins can be a valuable guide to nutritional status, although care is needed when interpreting the results of such tests in the alcoholic. Sensitive microbiological and biochemical tests for assessing vitamin status in man have been available for some years, and in addition, new biochemical methods are constantly being developed. It is important that such methods are evaluated, and possibly adapted for clinical use where appropriate. Newer methods may have significant advantages over older, more established techniques. For thiamine and pyridoxine, for example, methods now exist to determine accurately circulating levels of the active forms of these vitamins, which could give more direct assessment of vitamin status than earlier methodology that uses indirect measurements, such as red cell enzyme activities. On the other hand, in the case of folate and B12, there has been a tendency to opt for the easy-to-perform radioassay techniques, when in fact the earlier microbiological methods offer greater sensitivity and probably also better accuracy. Technically difficult assays should not be disregarded if they can give information which is of greater clinical use than a simpler assay technique. Clinical laboratories should always bear in mind what their vitamin methods are actually measuring, particular consideration being given to whether metabolically inactive forms or analogues are determined in the assay. This can be of importance to the interpretation of vitamin data in the alcoholic, who often has problems forming active vitamins from their precursors.(ABSTRACT TRUNCATED AT 400 WORDS)

Alcoholism↗
PubMed1984

Heterogeneity of human erythrocyte transketolase: a preliminary report.

A modified procedure for the preparation of transketolase from erythrocytes by dialysis and column ion-exchange resin chromatography is described. Changes have been made in the resin used, the column dimensions and the elution procedure so as to separate the enzyme with improved resolution, prepare the apoenzyme free of thiamine pyrophosphate and study the kinetics of its activation or reactivation by the coenzyme. On the basis of the elution profile of the enzyme activity from the chromatographic column, two different samples of the transketolase have been isolated, which differ not only in their isoelectric properties, but also in the proportion of the transketolase present in the apoenzyme form. Not only do the apoenzymes isolated from each of the two fractions differ in the way in which they recombine with thiamine pyrophosphate but kinetic analysis of the results shows that each fraction contains at least two variants of transketolase differing in their affinity for thiamine pyrophosphate. Three, probably four, separate variants have been identified which differ in their affinities for thiamine pyrophosphate over a range greater than 10(4). It is concluded that these two fractions of the enzyme must contain different subsets of the eight isoenzymes of transketolase of differing isoelectric points and that some of these isoenzymes must differ also in their affinity for the coenzyme. The implications of these findings for the Blass and Gibson hypothesis about the pathogenesis of the Wernicke-Korsakoff syndrome are considered.

Alcohol Amnestic Disorder↗
PubMed1984

Differential effect of chronic alcohol intake and poor nutrition on body weight and fat stores.

A six-months out-patient study of chronic alcoholics with undecompensated liver disease has shown a statistically significant inverse correlation between the change in mean corpuscular volume and the change in body weight (r = -0.4, P less than 0.01). A fall in body weight over this period was the best clinical indicator of apparently continuing alcohol abuse. Previous anthropometric studies have indicated that reduced adipose tissue is one cause of lower body weights in such patients. To determine whether this is due to the effects of alcohol or of poor nutrition, the epididymal fat pad weights of rats following 28 days administration of alcohol (36% of total calories) as part of a nutritionally adequate liquid diet were compared with those of pair-fed controls initially matched for body weight. At the end of the experiment, body weight gain was the same in both groups but the mean weight of the fat pads of alcohol-fed animals (371.7 mg +/- 60.0 mg SD) all of which developed hepatic steatosis was 29% greater than that of pair-fed controls (288.7 mg +/- 42.4 mg). This difference was statistically significant (P less than 0.025). This study shows that alcohol intake per se does not prevent an increase in body weight or fat even if hepatic steatosis is induced and that loss of adipose tissue in chronic alcoholics who continue to drink is probably due to simultaneous inadequate nutritional intake.

Adipose Tissue↗
PubMed1983

Biochemical mode of action of a hepatoprotective drug: observations on (+)-catechin.

(+)-Catechin inhibits the hepatic lipid accumulation resulting from chronic ethanol ingestion in the rat. Experiments have been carried out to determine the mechanisms underlying this effect. Ethanol was administered (2.0 g/kg intraperitoneally) to Wistar rats and 90 min later 1 microCi [U-14C] palmitic acid injected intraperitoneally. Animals were sacrificed 10 min after injection of palmitate and the liver freeze-clamped. Ethanol caused a 250% increase in the hepatic lactate:pyruvate (L:P) ratio and a 100% increase in the amount of [U-14C] palmitate incorporated into the hepatic lipids when compared with controls. Pretreatment of animals with (+)-catechin (200 mg/kg orally) at 24 and 0 hr before ethanol caused significant reductions in the L:P ratio and amount of radioactivity incorporated into hepatic lipids, when compared with animals receiving ethanol alone. (+)-Catechin also stimulated 14CO2 production from [1-14C] palmitate by liver slices taken from rats 90 min after ethanol administration. Thus, (+)-catechin appears to mediate its effect on fat accumulation partly by correcting the ethanol-induced alterations in hepatic redox state as there is no evidence of the drug inhibiting ethanol metabolism.

Animals↗
PubMed1983

Changes in plasma amino acid patterns in chronic alcoholic patients during ethanol withdrawal syndrome: their clinical implications.

Changes or imbalances in plasma amino acid patterns during withdrawal from ethanol were recorded in six randomly selected male chronic alcoholic patients (age range 23-47 years). Duration of drinking ranged from 4-15 years and their average daily amount of ethanol intake was more than 100G. Plasma amino acids (taurine, threonine, serine, glutamate, glutamine, proline, glycine, alanine, cysteine, valine, methionine, isoleucine, leucine, tyrosine, phenylalanine, histidine, tryptophan, ornithine, lysine and arginine) were estimated by autoanalyzer in all patients on admission before starting conventional detoxification therapy for ethanol withdrawal syndrome, and during therapy on day 3 and day 6. On admission, there was a statistically significant rise in the plasma levels of almost all aminoacids, particularly glutamate, glutamine, phenylalanine, proline, glycine, methionine, cysteine, lysine, tyrosine, valine, isoleucine, leucine, serine, threonine, alanine and arginine (in comparison to those of normal controls) in five out of six patients. During the following six days of treatment and total abstinence, the pattern of plasma aminoacid levels did not change significantly despite considerable clinical improvement. Plasma tryptophan levels were undetectable in all patients on admission, day 3 and also on day 6 except in one patient with lesser amount and shorter duration of drinking, the levels just returned to within normal range only on day 6. Plasma levels of histidine and taurine were found to be slightly lower than normal.

Adult↗