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T K Li

Publications and source records attributed to T K Li.

At least 235 records · Page 13Linked to original sources
PubMed1987

Persistence of tolerance to a single dose of ethanol in the selectively-bred alcohol-preferring P rat.

The persistence of tolerance to a single dose of ethanol was examined in the selectively-bred alcohol-preferring P line of rats. Tolerance was measured by a test that required trained rats to jump onto a descending platform to avoid footshock. On day 0, each trained rat received a single IP injection of 2.5 g ethanol/kg body weight and was tested every 15 minutes for recovery to a criterion of 75% of pre-alcohol training performance. The second ethanol injection of 2.5 g/kg and testing were carried out seven days later for one group (n = 12), and 14 days later for another group (n = 12). Tolerance was assessed by the differences in time required to recover to criterion performance and blood alcohol concentrations (BACs) at time of recovery on day 0 vs. day 7 and day 14. The mean recovery times and BACs on day 0 were 156 +/- 5 minutes and 222 +/- 6 mg%, respectively. The group injected on day 7 exhibited shorter recovery times of 113 +/- 4 minutes and higher BACs at recovery of 261 +/- 4 mg%, while the group injected on day 14 did not show any significant differences from the values obtained on day 0. In a second experiment, the persistence of tolerance in P rats was compared with that of rats from the alcohol-nonpreferring NP line and of stock Wistar rats (n = 6/group). All rats were trained and tested for recovery to criterion after 2.5 g ethanol/kg on day 0 as described for the first experiment. The rats were then injected with ethanol and tested for tolerance on three subsequent occasions.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Drinking↗
PubMed1987

Chronic ethanol tolerance through free-choice drinking in the P line of alcohol-preferring rats.

The objective of this study was to determine if the selectively bred P line of alcohol-preferring rats would develop behavioral (neuronal) tolerance with free-choice drinking of ethanol. Adult, male P rats were divided into four groups. One group (FCE) received food, water and a 10% (v/v) ethanol solution ad lib, while the control group (C) had only food and water. The other two groups received either a liquid diet containing 5% (v/v) ethanol (LDE) or a control liquid diet (LDC). All groups were kept on their respective feeding regimens for 14 days. The mean (+/- SEM) ethanol intakes for the FCE and LDE groups were 6.8 +/- 0.5 and 9.9 +/- 0.4 g ethanol/kg body wt./day, respectively. A shock-motivated jumping task was used to test for tolerance. Each rat received an IP injection of 2.5 g ethanol/kg and was tested every 15 minutes for recovery to a criterion of 75% of the performance level achieved with training. All rats were tested twice, once on the day before beginning their feeding regimens (day 0) and again 14 days later. Tolerance was assessed from differences in time of recovery to criterion performance and in blood alcohol concentrations (BACs) at recovery on day 0 vs. day 14. The mean recovery times for the C, FCE, LDC, and LDE groups on day 0 were 177 +/- 6, 170 +/- 6, 143 +/- 10 and 153 +/- 13 minutes, respectively, and the BACs were 219 +/- 6, 222 +/- 5, 220 +/- 19 and 214 +/- 6 mg%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Drinking↗
PubMed1987

Contents of monoamines in forebrain regions of alcohol-preferring (P) and -nonpreferring (NP) lines of rats.

The contents of monoamine neurotransmitters and metabolites were assayed in the frontal cortex, nucleus accumbens and anterior striatum of rats from the selectively bred alcohol-preferring P and nonpreferring NP lines. Lower levels of serotonin (20-30%) in all three brain regions of P as compared with NP rats lends support to the hypothesis that a decreased metabolic activity and/or innervation by serotonin neurons is associated with the abnormally high volitional intake of ethanol. Of additional interest, however, were the approximately 25% lower contents of dopamine and its major metabolites in the nucleus accumbens of the P rats. This observation may indicate that P rats have a specific deficiency in the dopaminergic projections from the ventral tegmental area to the nucleus accumbens and, since the accumbens is an important structure in brain reward circuitry, it might also be an important determinant of the excessive volitional intake of alcohol by P rats.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1987

Ethanol metabolism.

Alcohol is metabolized by two pathways in humans: the ADH pathway which accounts for the bulk of the metabolism, and the MEOS pathway which contributes to the increased rate of ethanol elimination at high blood alcohol levels. The increased rate of elimination which results from chronic alcohol consumption is due to an increase in MEOS activity. The activities of these pathways are influenced by environmental factors such as smoking, diet, and endocrine factors. In addition, individuals inherit different types of ADH isoenzymes which have different kinetic properties. Individuals with different phenotypic variants, e.g. the beta 1 vs beta 2 isoenzymes, appear to have different rates of ethanol elimination. The cloning of the ADH genes and the availability of molecular hybridization methods now make it possible to genotype individuals and to correlate the genotype with both alcohol elimination rates and with the risk of developing medical complications of alcoholism or even of developing alcoholism itself.

Alcohol Dehydrogenase↗
PubMed1987

Purification of human liver aldehyde dehydrogenase by high-performance liquid chromatography and identification of isoenzymes by immunoblotting.

Human liver aldehyde dehydrogenase (ALDH) exists in multiple molecular forms. Two different isoenzymes of ALDH have been purified which will oxidize acetaldehyde to acetate. ALDH1 is localized principally in hepatocyte cytosol and exhibits a Km for acetaldehyde of about 0.1 mM at pH 9.5. ALDH2 is mitochondrial in origin and exhibits low Km for acetaldehyde, about 1 microM. We have developed rapid purification procedures for ALDH1 and ALDH2 by use of agarose-AMP affinity chromatography and high-performance anion-exchange liquid chromatography (HPLC). The method takes less time and affords higher yields of the labile ALDH isoenzymes than conventional column chromatography methods. A previously uncharacterized ALDH form has been identified by anion-exchange HPLC which exhibits high Km for acetaldehyde, about 1 mM, and is very labile. Polyclonal antibodies to the purified ALDH1 and ALDH2 isoenzymes have been prepared. As evidenced by immunoblotting of starch gels containing the purified isoenzymes, anti-ALDH1 does not crossreact with ALDH2 and anti-ALDH2 does not crossreact with ALDH1. The anti-ALDH2 antibody identifies the "inactive" variant of ALDH2 in Japanese livers exhibiting the "deficient" ALDH2 phenotype. The sensitivity of detection of ALDH isoenzymes in liver homogenate-supernatants by immunoblotting of starch gels is about 10-fold greater than that by activity staining.

Aldehyde Dehydrogenase↗
PubMed1987

Alcoholism: is it a model for the study of disorders of mood and consummatory behavior?

Depression, eating disorders, and carbohydrate craving are frequently seen in alcoholics or recovering alcoholics. Accordingly, these disorders may share some mediating pathways. It is now well-established that there is a genetic predisposition to alcoholism. Through genetic means, our laboratory has developed an animal model of alcoholism. Free-fed Wistar rats were selectively bred for the traits of alcohol-preference (the P line) and non-preference (the NP line). After more than 20 generations of selection, the lines show a stable difference of more than six-fold in voluntary ethanol consumption. We have now shown that the P line satisfies all the perceived requirements of an animal model of alcoholism. One major discovered difference between the P and the NP line is the lowered content of serotonin in certain brain regions of the P rats. Interestingly, fluoxetine curbs the alcohol-seeking behavior of the P rats; variation in the carbohydrate content of the diet, however, does not modify voluntary ethanol intake. The P rats are similar in body weight to the NP rats, but are more active in a novel environment than the NP rats.

Alcohol Drinking↗
PubMed1987

Catalytic properties of human liver alcohol dehydrogenase isoenzymes.

Human liver alcohol dehydrogenase (ADH) exists in multiple molecular forms which arise from the association of eight different types of subunits, alpha, beta 1, beta 2, beta 3, gamma 1, gamma 2, pi, and chi, into active dimeric molecules. A genetic model accounts for this multiplicity as products of five gene loci, ADH1 through ADH5. Polymorphism occurs at two loci, ADH2 and ADH3, which encode the beta and gamma subunits. All of the known homodimeric and heterodimeric isoenzymes have been isolated and purified to homogeneity. Analysis of the steady-state kinetic properties and substrate and inhibitor specificities has shown substantial differences in the catalytic properties of the isoenzymes. For example, the Km values for NAD+ and ethanol vary as much as 1,000-fold among the isoenzymes. Some of the differences in catalytic properties can be related to specific amino acid substitutions in the ADH isoenzymes.

Alcohol Dehydrogenase↗
PubMed1987

Alcohol preference and regional brain monoamine contents of N/Nih heterogeneous stock rats.

The N/Nih heterogeneous stock rats were tested for alcohol drinking behavior. Rats that met criteria for high (greater than 5.0 g ethanol/kg body weight/day) and low (less than 0.5 g/kg/day) alcohol consumption were chosen, and the regional brain contents of monoamine neurotransmitters were determined in these animals. The primary finding was a lower content of serotonin and 5-hydroxyindoleacetic acid in the thalamus and hypothalamus of the high alcohol preferring N/Nih rats as compared with the low preferrers. The high preferrers were also found to have a lower content of dopamine and norepinephrine in the thalamus. The findings support the hypothesis that an inverse relationship exists between the density and/or metabolic functioning of regional brain serotonin systems and alcohol preference.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1987

Naloxone attenuation of voluntary alcohol consumption.

The effect of naloxone on voluntary alcohol consumption was examined in two lines of rats which have recently been selectively bred for oral alcohol preference (High Alcohol Drinking or HAD line) or aversion (Low Alcohol Drinking or LAD line). Genetic differences in brain met-enkephalin content were examined in two additional lines of rats which have been genetically selected for oral alcohol preference (Alcohol-Preferring or P line) or aversion (Alcohol-Nonpreferring or NP line).

Alcohol Drinking↗
PubMed1987

Rodent lines selected for factors affecting alcohol consumption.

The selectively bred alcohol-preferring P and alcohol-nonpreferring NP lines of rats have been used to study the biology of alcohol-seeking behavior. The P rats satisfy all the perceived criteria for an animal model of alcoholism: free-fed animals voluntarily drink alcoholic solutions (10-30% v/v) to intoxication; they acquire metabolic and neuronal tolerance, and develop physical dependence; they work (bar-press) to obtain the alcohol and self-administer ethanol intragastrically. Drinking in the P rats ceases when blood alcohol concentrations (BACs) reach 50-70 mg%, but BACs subsequently rise to as high as 270 mg%. BACs, 15-70 mg%, elicit increased spontaneous motor activity in the P rats, but not in the NP rats. Acute tolerance to a single hypnotic dose of ethanol develops more rapidly and persists many days longer in the P than in the NP rats. These differences in the effects of ethanol may underlie the disparate alcohol drinking behaviors of the P and NP rats. The P rats also exhibit lowered serotonin levels in certain brain regions. Serotonin reuptake inhibitors curtail the alcohol drinking of the P rats, suggesting a role for serotonin in alcohol preference.

Alcohol Drinking↗
PubMed1986

Role of the pituitary and neonatal androgenic imprinting in the hormonal regulation of liver alcohol dehydrogenase activity.

Liver alcohol dehydrogenase activity is increased by thyroidectomy, orchidectomy, or hypophysectomy. We investigated the mechanisms of these hormonal effects by examining the effects of testosterone, dexamethasone and thyroid hormone on liver alcohol dehydrogenase activity in hypophysectomized rats and in cultured hepatocytes, and the effect of administration of androgens to neonatal female rats. Testosterone did not lower alcohol dehydrogenase activity in hypophysectomized rats, whereas dexamethasone and thyroxine produced moderate decreases in activity. Triiodothyronine reduced alcohol dehydrogenase activity of cultured hepatocytes from male and hypothyroid female rats in a dose-dependent fashion, confirming that thyroid hormone had pituitary-independent effects on the enzyme activity. Dexamethasone was required for the expression of alcohol dehydrogenase activity in cultured cells, and it increased the enzyme activity when present at supraphysiologic concentrations. Treatment of neonatal female rats with testosterone reduced the activity of the enzyme in adulthood. The difference in alcohol dehydrogenase activity in adult male and female rats appears to be determined in part by neonatal imprinting by androgens and in part by an effect of testosterone that is either mediated by or dependent upon the pituitary. Thyroid hormone reduces alcohol dehydrogenase activity by a direct effect on the liver.

Adrenalectomy↗
PubMed1986

Selective carboxymethylation of cysteine-174 of the beta 2 beta 2 and beta 1 beta 1 human liver alcohol dehydrogenase isoenzymes by iodoacetate.

The beta 1 beta 1 and beta 2 beta 2 human liver alcohol dehydrogenase isoenzymes differ by only one residue at the coenzyme-binding site; Arg-47 in beta 1 is replaced by His in the beta 2 subunit. Since Arg-47 is thought to facilitate the carboxymethylation of Cys-46 in horse liver alcohol dehydrogenase by binding halo acids in a Michaelis-Menten complex prior to inactivation, the specificity and kinetics of modification of the two human liver beta beta isoenzymes with iodoacetate were compared. Both of the beta beta isoenzymes were inactivated by treatment with iodo[14C]acetate, and one Cys per subunit was carboxymethylated. Cys-174, which is a ligand to the active-site zinc atom in horse liver alcohol dehydrogenase, was selectively carboxymethylated in each of the human beta beta isoenzymes; less than 15% of the iodo[14C]acetate incorporated into the enzyme appeared in Cys-46. Therefore, the three-dimensional structure of the basic amino acids in the anion-binding site of the human beta beta isoenzymes appears to be different from that of horse liver alcohol dehydrogenase. The kinetics of alkylation are consistent with the formation of a Michaelis-Menten complex before inactivation of the isoenzymes. The average Ki values for iodoacetate were 10 and 16 mM for beta 1 beta 1 and beta 2 beta 2, respectively, and maximal rate constants for inactivation were 0.22 and 0.17 min-1, respectively. From these data, it can be concluded that there is a relatively minor effect of the substitution of His for Arg at position 47 on the kinetics of inactivation.

Alcohol Dehydrogenase↗
PubMed1986

The development of metabolic tolerance in the alcohol-preferring P rats: comparison of forced and free-choice drinking of ethanol.

Experiments were performed to determine whether metabolic tolerance to alcohol develops in the alcohol-preferring P rats during free-choice drinking. In Experiment 1, alcohol elimination rates (AERs) in female Wistar and P rats were measured as a function of age from 26 to 180 days old. AERs calculated as mmol hr-1 per kg body weight fell with age, whereas AERs expressed as mmol hr-1 per rat increased to reach a constant value after 60 days of age. These data indicate that the chronic effects of ethanol on AER are most easily interpreted if experiments are performed in animals 60 days of age or older and AERs are calculated as mmol hr-1 per rat. In Experiments 2 and 3, P female rats were exposed to alcohol for 6-7 weeks either by free-choice drinking or by forced feeding with liquid diets. With free-choice drinking of alcohol, solid food containing 31 percent of the calories as protein, 10 percent ethanol (v/v) and water were made available ad lib. The liquid diets used for forced ethanol feeding were the Bio-Serv-711 diet, a protein-supplemented Bio-Serv-711 diet and the AIN diet and they contained 18, 32 and 22 percent calories as protein, respectively. When compared with pair-fed or ad lib controls, all the P rats exposed to alcohol by either free-choice or forced-feeding exhibited increased AERs (i.e., metabolic tolerance) after 6-7 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Dehydrogenase↗
PubMed1986

Effect of low dose ethanol on spontaneous motor activity in alcohol-preferring and -nonpreferring lines of rats.

To determine if behavioral arousal may be associated with ethanol preference, the effects of low to moderate doses of ethanol on spontaneous motor activity (SMA) were studied in the selectively bred alcohol-preferring (P) and -nonpreferring (NP) lines of rats as well as in the Maudsley Reactive (MR/N) and Nonreactive (MNR/N) strains. Alcohol-naive rats had food and water available ad lib, but food was removed 24 hr before and during activity testing. After an intraperitoneal injection of saline (5 ml) or ethanol (0.12 to 1.5 g/kg), SMA was monitored every three min for 30 min in an electronic activity monitor. The P and MR/N rats exhibited increased SMA after doses of 0.12 and 0.25 g/kg. Both the NP and MNR/N rats failed to show increased SMA at any ethanol dose. Moderate doses of ethanol, 1.0 and 1.5 g/kg, consistently depressed SMA in all lines/strains. In 24 hr-fasted rats, increased SMA occurred within 6-12 min after injection, but free-fed rats exhibited increased SMA 12-24 min after an ethanol dose of 0.25 g/kg. Free-choice drinking scores (10% ethanol (v/v) versus water) for the P, MR/N, MNR/N and NP rats were 6.6 +/- 0.5, 4.9 +/- 0.8, 2.2 +/- 0.7 and 1.4 +/- 0.3 g ethanol/kg body wt/day (mean +/- SEM), respectively. The data indicate a positive relationship between ethanol preference and ethanol-induced motor stimulation and suggest that hyperactivity may be an expression of the positive reinforcing effect of ethanol for alcohol-preferring rats.

Animals↗
PubMed1986

Genetic variability of enzymes of alcohol metabolism in human beings.

Alcohol is eliminated from the body almost entirely by hepatic metabolism, first to acetaldehyde, then to acetate, and finally to carbon dioxide and water. The time course of elimination is best described by Michaelis-Menten kinetics, and rates of elimination following standard doses of ethanol vary among subjects as much as three-fold. Studies comparing rates of elimination in identical and fraternal twins have shown that about half of the variability is attributable to genetic factors. The principal enzymes responsible for ethanol metabolism are alcohol dehydrogenase and aldehyde dehydrogenase. The reaction catalyzed by alcohol dehydrogenase is the rate-limiting step of the pathway. Human livers contain multiple isoenzymes of alcohol dehydrogenase, which are dimeric molecules arising from the association of two subunits encoded by five different structural genes. Genetic polymorphism at two of these gene loci has been described, and all known homo- and heterodimeric forms of the isoenzymes have now been isolated and characterized. Notably, some of them differ quite strikingly in reactivity toward ethanol. Thus a basis for the genetic variability in alcohol metabolic rate can be found in the kinetic properties of the alcohol dehydrogenase isoenzymes. The efficient oxidation of acetaldehyde by hepatic aldehyde dehydrogenase is essential for ethanol oxidation to continue over time, because the equilibrium of the alcohol dehydrogenase reaction favors the conversion of acetaldehyde to ethanol. Acetaldehyde is a very toxic substance the removal of which makes possible the consumption of large quantities of ethanol frequently imbibed by alcoholics. There are also multiple molecular forms of aldehyde dehydrogenase in liver, and the mitochondrial form is the one principally responsible for acetaldehyde oxidation.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaldehyde↗
PubMed1986

Transport and metabolism of vitamins.

Although the biochemical roles of most vitamins in the body are reasonably well understood, our knowledge of how the body transports and metabolizes the vitamins is incomplete. This paper summarizes the information available on riboflavin, vitamin B-6, biotin, vitamin D, vitamin C, and pantothenic acid. As might be expected on the basis of the diverse chemistry and biology of these substrates, the body has quite unique mechanisms for handling each of them.

Animals↗