Biomedical subjects

T K Li

Publications and source records attributed to T K Li.

At least 163 records · Page 9Linked to original sources

PubMed1995

Rat mitochondrial aldehyde dehydrogenase polymorphism and major histocompatibility complex RT1.A phenotypes are not associated with alcohol drinking in P and NP rats.

Previous studies revealed polymorphisms in mitochondrial aldehyde dehydrogenase (ALDH2) and the major histocompatibility complex RT1.A that appeared in association with alcohol drinking preference in the alcohol-preferring (P) and alcohol-nonpreferring (NP) rat lines. To determine the strength of these associations, the P and NP lines were crossed, and cosegregation studies were performed in the F2 progeny. The ALDH2Q allele and the ALDH2R allele, found in the P and NP lines, respectively, were found not to be associated with the high and low drinking animals in the F2 progeny. Kinetic studies with ALDH2Q and ALDH2R isozymes purified from the mitochondria of P and NP rat livers, respectively, showed that the polymorphism would not be expected to be associated with altered aldehyde metabolism. The association between RT1.A and alcohol preference (RT1.Auu with high and RT1.AII with low alcohol intake) also could not be confirmed in the segregating F2 progeny of the P x NP intercross.

Alcohol Drinking↗

PubMed1995

Pharmacogenetic models of alcoholism.

This article reviews recent efforts in developing laboratory animal models for the study of alcoholism and abnormal alcohol-seeking behavior. Through selective breeding, stable lines of rats that reliably exhibit high and low voluntary alcohol consumption have been raised. The high preference animals self-administer ethanol by free-choice drinking, and operantly for intragastric infusion, in amounts that produce intoxication. With chronic free-choice drinking, the preferring rats develop tolerance and physical dependence. Low to moderate concentrations (50-150 mg%) of ethanol are reinforcing to the preferring rat, as evidenced by intracranial self-administration studies. Compared with nonpreferring animals, they are less affected and develop tolerance more quickly to the sedative-hypnotic effects of ethanol. Neurochemical, -anatomical and -pharmacological studies indicate innate differences between the alcohol-preferring and -nonpreferring lines in the brain limbic structures. Depending on the animal model under study, a change in the main dopaminergic pathway and/or the serotonergic, opioid, and GABAergic systems that regulate this pathway may underlie the vulnerability to the abnormal alcohol-seeking behavior in these pharmacogenetic animal models of alcoholism.

Alcoholism↗

PubMed1994

Opioid involvement in alcohol drinking.

A large body of evidence indicates that the endogenous opioid system plays an important role in maintaining alcohol drinking behavior. Evidence is reviewed that indicates that the reinforcing properties of alcohol that lead to continued and repeated bouts of drinking may be due, in part, to alcohol-induced activation of the endogenous opioid system. Much of this evidence is pharmacologic in nature. Blocking the action of endogenous opioid peptides via administration of opioid antagonists significantly attenuates alcohol consumption in animals under a variety of experimental conditions. In clinical trials, opioid receptor antagonists decrease alcohol consumption, relapse rates, subjective high, and alcohol craving in outpatient alcoholics. The potential clinical utility of opioid receptor antagonists in the treatment of alcoholism and alcohol dependence is discussed.

Alcohol Drinking↗

PubMed1994

Comparative roles of histidine 51 in human beta 1 beta 1 and threonine 51 in pi pi alcohol dehydrogenases.

Histidine at position 51 of the class I beta 1 alcohol dehydrogenase (ADH) functions as a general base by indirectly abstracting a proton from the alcohol substrate through a hydrogen-bonded proton relay system. The human class II pi-ADH was reported to be polymorphic, having either Ser or Thr, but not His at position 51. It is unknown whether Ser or Thr51 have a catalytic role in ethanol oxidation with pi-ADH. Accordingly, we expressed and purified recombinant mutants of pi-ADH with Thr, Ser, and His at position 51. At pH 6.5, values for Vmax/Km for ethanol were 0.30, 0.10, and 0.09 min-1 mM-1 for pi 51Thr, pi 51Ser, and pi 51His ADH, respectively. Hence the effects of the substitutions were much less than the 11-fold decrease in Vmax/Km observed for beta 1-ADH when a neutral amino acid (Gln) was substituted for His51. Addition of a buffer base (400 mM glycylglycine) had little effect on Vmax/Km of recombinant pi 51Thr or pi 51Ser ADH, while it increased Vmax/Km for ethanol 7-fold for the beta (1)51 Gln ADH. We conclude that there is no evidence for Thr51 of pi-ADH participating in a proton relay similar to that seen in beta 1-ADH and that a base at position 51 may not be a universal requirement for a functional alcohol dehydrogenase with a moderate efficiency for ethanol oxidation at a physiological pH.

Alcohol Dehydrogenase↗

PubMed1994

The benzodiazepine inverse agonist RO19-4603 exerts prolonged and selective suppression of ethanol intake in alcohol-preferring (P) rats.

The time course of the benzodiazepine (BDZ) inverse agonist RO19-4603 in antagonizing ethanol (EtOH) intake was investigated in alcohol-preferring (P) rats (n = 7) maintained on 24-h continuous free-choice access to EtOH (10% v/v), water, and food. After fluid intakes had stabilized over several weeks, animals were injected with Tween-80 vehicle solution or RO19-4603 (0.075, 0.150, and 0.30 mg/kg). EtOH and water intakes were determined at 8- and 24-h intervals. RO19-4603 caused a marked attenuation of EtOH drinking with each of the doses tested. EtOH intake during the 8-h following 0.075, 0.150, and 0.30 mg/kg RO19-4603 was decreased by approximately 36, 74, and 57%, respectively. Intakes during the 24-h interval were similar to the vehicle control condition. However, 32 h post-drug administration, EtOH intakes were reduced to approximately 27, 31, and 29% following the 0.075, 0.150 and 0.30 mg/kg doses, respectively. To further confirm the reliability of the RO19-4603 dose-response effect, and its selectivity for EtOH, the highest dose condition (0.30 mg/kg) was tested twice. The second 0.30 mg/kg dose condition exerted a profile of effects similar to the initial treatment; 8 h following administration, intake was decreased to 60% of the control level, and 32 h post-drug administration intake was decreased to approximately 46% of the controls. These decreases were evidently selective in comparison with water, since water drinking showed compensatory increases which paralleled the decreased EtOH consumption. Dose-response comparisons indicated that 0.150 mg/kg approaches the maximum effective dose, since the 0.30 mg/kg dose of RO19-4603 did not produce an additional decrease in EtOH intake.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Deterrents↗

PubMed1994

Regional serotonin1A receptors in the CNS of alcohol-preferring and -nonpreferring rats.

The densities of serotonin1A (5-HT1A) receptors, labeled with [3H]8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), were examined in the CNS of alcohol-naive adult male alcohol-preferring (P) and -nonpreferring (NP) rats using quantitative autoradiography. The densities of sites labeled with 2 nM [3H]8-OH-DPAT were a) 20-30% higher in the medial prefrontal, frontal (layers 1, 2, and layers 3-6), parietal (layers 3-6), and cingulate cortex; b) 35-40% higher in the retrosplenial, occipital (all layers), temporal (all layers) cortex; and c) 15% higher in the entorhinal cortex of the P compared with the NP rat. Within the hippocampus, significant differences between the rat lines were observed only in the posterior portion where the densities of [3H]8-OH-DPAT labeled sites were a) 10-15% higher in the dorsal dentate gyrus, dorsal CA1, and dorsal CA3 regions; and b) 15-25% higher in the anterior ventral hippocampal area and ventral dentate gyrus of the P relative to the NP line. In contrast to the above results, the densities of [3H]8-OH-DPAT labeled sites were 15-20% lower in the dorsal, paradorsal, and median raphe nuclei of the P compared with the NP rat. No differences in [3H]8-OH-DPAT binding between the rat lines were found in several basal ganglia, limbic, and brain stem regions. The data indicate that there are greater numbers of postsynaptic 5-HT1A receptors in certain parts of the cerebral cortex and hippocampus of the P compared with the NP rat.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1994

Heritable features of the auditory oddball event-related potential: peaks, latencies, morphology and topography.

Baseline auditory ERP data from a larger study of the genetic determinants of the response to alcohol were collected from 59 monozygotic (MZ) twin pairs and from 39 same-sex dizygotic (DZ) twin pairs who drank socially. Three methods for measuring genetic influence on the ERPs were applied. First, based on maximum-likelihood estimates, the heritability of conventional peak amplitude and latency of N1 and P3 components was computed for each of 16 lead locations using tests of the significance of heritability based on intraclass correlations. P3 amplitude provided the strongest results, distributed symmetrically over caudal leads, and implied gene dominance as the mode of genetic transmission for the P3 component. A substantial genetic influence on N1 latency suggested a mixture of additive and dominance effects in the left fronto-temporal regions. N1 amplitude measures trended towards significant heritability, but none was observed for P3 latency. The second method used the maximum of the cross-correlation function to compare wave form shape in a lead-by-lead analysis of data from cotwins. Genetic influence was apparent in both target and non-target ERP responses, with a fronto-central topography of significant results. The third method reduced all spatial and temporal ERP differences from a pair of twins to a single scalar number for each response. Distributions of this global measure revealed significant genetic influence on both non-target and target ERPs. A post hoc analysis of the effect of gender on the heritability of N1 or P3 peaks and latencies revealed no statistically significant observations in this sample of young adult twins.

Acoustic Stimulation↗

PubMed1994

Effects of MK 801 and diazepam on the EEG of P and NP rats.

The selectively bred alcohol-preferring (P) and alcohol-nonpreferring (NP) rats have been shown to possess a number of behavioral and electrophysiological differences in response to alcohol. We sought to evaluate whether or not P and NP rats would respond differently to other sedative-hypnotic drugs related to ethanol. EEG recordings were conducted following systemic administration of the NMDA receptor antagonist MK 801 (0.1 mg/kg, ip) and the GABA/benzodiazepine receptor complex agonist diazepam (1.5 mg/kg, ip). Nine P and nine NP rats was implanted with bipolar stainless steel electrodes in the frontal cortex, the dorsal hippocampus, the ventral thalamus, and the anterior amygdala. In the vehicle condition, P rats showed significantly greater power of the EEG in the slow frequencies as compared with NP rats in the frontal cortex. Furthermore, P rats were found to have lower peak theta frequency (6-8 Hz) than NP rats in the frontal cortex, the dorsal hippocampus, and the ventral thalamus. MK 801 produced a significantly greater increase in the mean power of the EEG in NP rats in the 8-16 Hz than in P rats, whereas diazepam was found to decrease theta peak frequency (6-8 Hz), but more so in NP rats that in P rats. These data suggest that, in addition to differential responsiveness to alcohol, P and NP rats also differ in response to drugs that modify GABA and glutamate neurotransmission.

Alcoholism↗

PubMed1994

Consumption of sweet, salty, sour, and bitter solutions by selectively bred alcohol-preferring and alcohol-nonpreferring lines of rats.

To determine whether selective breeding for high or low oral ethanol consumption is associated with different preferences for nonpharmacological solutions with various flavors, the oral intake of a range of concentrations of sucrose (0.5-64.0 g/100 ml), NaCl (0.025-3.2 g/100 ml), citric acid (0.008-2.048 g/liter), and sucrose octaacetate (0.002-0.512 g/liter) was studied in alcohol-preferring (P) and alcohol-nonpreferring (NP) rats. Separate groups of 7-8 rats from each line were tested for consumption of each of the four flavors. The flavored solutions were presented continuously with water and food always available, and the concentrations were doubled every 48 hr. Although rats from both lines showed a strong preference for the sucrose solutions, P rats consumed greater amounts than NP rats [F(7,98) = 5.57, p < 0.001]. Rats of the P line drank less of the NaCl solutions than NP rats [F(7,98) = 3.88, p < 0.001], but the effect was not as robust as the line differences seen with sucrose. The P and NP rats did not differ in citric acid or sucrose octaacetate intake at any of the concentrations tested. Selective breeding for high oral ethanol preference appears to be positively associated with consumption of sweet solutions and negatively associated with intake of salty solutions.

Alcohol Drinking↗

PubMed1994

Reduced serotonergic immunoreactive fibers in the forebrain of alcohol-preferring rats.

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 in the alcohol abuse is discussed.

Alcohol Drinking↗

PubMed1994

Catalytic efficiency of human alcohol dehydrogenases for retinol oxidation and retinal reduction.

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 relative efficiency (V/Km) of eight human ADH isoenzymes for oxidation of all-trans-retinol and reduction of three retinal isomers (all-trans, 9-cis, and 13-cis-retinal). Class IV sigma sigma and class II pi pi isoenzymes are the most efficient forms, with V/Km values approximately 100 and 30 times greater, respectively, than class I beta 1 beta 1 or gamma 1 gamma 1, sigma sigma exhibits the highest V/Km (1-2 microns-1min-1), followed by pi pi, with V/Km of 0.5-0.6 microns-1min-1 for all-trans-retinol, all-trans-retinal, and 9-cis-retinal. pi pi also has the lowest Km (11-14 microns) for all-trans-retinol and three retinal isomers. alpha alpha shows an intermediate efficiency, with V/Km of 0.09-0.2 microns-1min-1 and a relatively low Km of 16-24 microns for all four substrates. alpha alpha has the highest efficiency of all tested isoenzymes for 13-cis-retinal. Class III chi chi is inactive with all the tested retinoids.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Dehydrogenase↗

PubMed1994

Low frequency of the ADH2*2 allele among Atayal natives of Taiwan with alcohol use disorders.

Genetic variation at two polymorphic alcohol dehydrogenase loci, ADH2 and ADH3, and at the polymorphic mitochondrial aldehyde dehydrogenase locus, ALDH2, may influence the risk of developing alcoholism by modulating the rate of elimination of ethanol and the rate of formation and elimination of acetaldehyde. Populations differ in allele frequencies at these loci. We determined the genotypes at all three of these loci in Atayal natives of Taiwan. The frequencies of ADH2*2, ADH3*1, and ALDH2*1 alleles (0.91, 0.99, and 0.95, respectively) were significantly higher among the Atayal than among a predominantly Han Chinese population from Taiwan. Among the Atayal, the group with alcohol use disorders (alcohol dependence and alcohol abuse) had a significantly lower frequency of the ADH2*2 allele (0.82) than those without alcohol use disorders (0.91). The ADH2*2 allele encodes the beta 2 subunit; isozymes containing beta 2 subunits oxidize alcohol faster in vitro than the beta 1 beta 1 isozyme encoded by ADH2*1. Thus, the simplest explanation for these data is that individuals with a beta 2 isozymes have a higher rate of ethanol oxidation, which is a deterrent to alcohol abuse and dependence in some individuals. The Atayal with alcohol use disorders also had a lower frequency of ALDH2*2 than the controls; this allele is known to be responsible for the alcohol-flush reaction among Asians, and thereby deters drinking.

Adult↗

PubMed1994

Daidzin, an antioxidant isoflavonoid, decreases blood alcohol levels and shortens sleep time induced by ethanol intoxication.

The extract from an edible vine, Pueraria lebata, has been reported to be efficacious in lessening alcohol intoxication. In this study, we have tested the efficacy of one of the major components, daidzin, from this plant extract. When ethanol (40% solution, 3 g/kg body weight) was given to fasted rats intragastrically, blood alcohol concentration (BAC) peaked at 30 min after alcohol ingestion and reached 1.77 +/- 0.14 mg/ml (mean values +/- SD, n = 6). If daidzin (30 mg/kg) was mixed with the ethanol solution and given to animals intragastrically, BAC was found to peak at 90 min after alcohol ingestion and reached only 1.20 +/- 0.30 mg/ml (n = 6) (p < 0.05 vs. controls). The ability of daidzin to delay and decrease peak BAC level after ethanol ingestion was also observed in fed animals. In both fasted and fed rats given alcohol without daidzin, BAC quickly declined after reaching its peak at 30 min. By contrast, BAC levels receded more slowly if daidzin was also fed to the animals. Daidzin showed a chronic effect. Rats fed daidzin for 7 days before ethanol challenge, but not on the day of challenge, also produced lower and later peak BAC levels. Interestingly, daidzin, whether fed to rats only once or chronically for 7 days, did not significantly alter activities of either alcohol dehydrogenase or mitochondrial aldehyde dehydrogenase in the liver. Further experiments demonstrated that daidzin shortened sleep time for rats receiving ethanol intragastrically (7 g/kg) but not intraperitoneally (2 g/kg). To test whether daidzin delayed stomach-emptying, [14C]polyethylene glycol was mixed with ethanol and fed to rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Dehydrogenase↗

PubMed1994

Genetic and neurobiological basis of alcohol-seeking behavior.

Through selective breeding, rat lines exhibiting high and low alcohol drinking preference have been developed as useful animal models for studying the neurobiological basis of alcohol-seeking behavior. The identified differences between lines in neurotransmitter functioning allows the evaluation of receptor agonist/antagonist compounds that might be efficacious in the treatment of alcohol craving and dependence.

Alcoholism↗

PubMed1994

Polymorphism of alcohol and aldehyde dehydrogenase genes and alcoholic cirrhosis in Chinese patients.

Liver alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), the principal enzymes responsible for the oxidation of ethanol, are polymorphic at the ADH2, ADH3 and ALDH2 loci in human beings. Our previous studies have shown that, compared with nonalcoholic individuals, Chinese alcoholic patients without liver disease had significantly lower frequencies of the ADH2*2 and ADH3*1 alleles, which encode high maximum velocity beta 2- and gamma 1-ADH subunits, respectively, as well as a lower frequency of the ALDH2*2 allele, which encodes an enzymatically inactive subunit. The data strongly suggest that genetic variation in both ADH and ALDH may influence drinking behavior and the risk of alcoholism developing through acetaldehyde formation. To further investigate the possible role of acetaldehyde in the pathogenesis of alcoholic liver disease, we determined the ADH and ALDH genotype frequencies in patients with alcohol-related cirrhosis (n = 27), viral hepatitis-related cirrhosis (n = 29) and gastric and duodenal ulcer without relevance to alcohol (n = 30). We developed a new restriction fragment length polymorphism method to genotype the mutant and normal ALDH2 alleles by using polymerase chain reaction-directed mutagenesis, which proved to be simpler and faster than the conventional detection methods that use hybridization with allele-specific oligonucleotide probes. We found that the frequencies of the alleles ADH2*2 (57%), ADH3*1 (78%) and ALDH2*2 (9%) in the alcoholic cirrhotic patients were significantly lower than those in the healthy controls and in the patients with cirrhosis from viral hepatitis and with gastric and duodenal ulcer.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Dehydrogenase↗

PubMed1993

Effect of prostaglandin E2 (PGE2) on IL-3/granulocyte-macrophage colony-stimulating factor production by T helper cells. Mode of stimulation and presence of costimulation can determine response to PGE2.

PGE2 is an immunomodulator that selectively inhibits the production of lymphokines associated with Th1 cells (IL-2 and IFN-gamma) but not Th2 cells (IL-4 and IL-5). We examined the effect of PGE2 on the production of IL-3 and granulocyte-macrophage (GM)-CSF from murine Th1 and Th2 clones. When the T cells were stimulated with Ag and APC, PGE2 inhibited IL-3/GM-CSF production from 3 Th1 clones and 1 Th2 clone, but enhanced production from 3 Th2 clones. A more specific bioassay demonstrated that IL-3 production was differentially affected by PGE2 in the Th clones. These data suggested that the effect of PGE2 on IL-3 production is dependent, not on a property of the lymphokine, but on a property of the T cell. The responsiveness to PGE2 did not consistently differ between Th1 and Th2 cells, and the observed heterogeneity in the response of Th2 clones did not correlate with the ability to induce increases in intracellular [Ca2+]. However, we postulated that signaling differences between the clones might explain the varied responsiveness to PGE2. If so, then the mode of stimulation might be expected to activate different pathways and thus affect the PGE2-responsiveness. Stimulation with ionomycin induced variable levels of IL-3/GM-CSF from the T cell clones. APC-derived costimulation dramatically enhanced IL-3/GM-CSF; the cells which produced high levels in response to ionomycin alone were not detectably costimulating each other. Interestingly, PGE2 enhanced IL-3/GM-CSF (and IL-3 alone in at least some cases) from cells stimulated with ionomycin alone, demonstrating that the mode of stimulation affects the PGE2-responsiveness. Addition of APC not only enhanced lymphokine production, but also altered the PGE2-responsiveness of the Th1 cells. In these cells, PGE2 either inhibited IL-3 and GM-CSF production or had no effect, in no case was the lymphokine production enhanced by PGE2 as it had been with ionomycin alone. These data indicate that the presence of APC-derived costimulatory signals can alter the effect of PGE2 on Th cell lymphokine production.

Animals↗

PubMed1993

Alcohol and aldehyde dehydrogenase polymorphisms and alcoholism.

The alcohol-flush reaction occurs in Asians who inherit the mutant ALDH2*2 allele that produces an inactive aldehyde dehydrogenase enzyme. In these individuals, high blood acetaldehyde levels are believed to be the cause of the unpleasant symptoms that follow drinking. We measured the alcohol elimination rates and intensity of flushing in Chinese subjects in whom the alcohol dehydrogenase ADH2 and ALDH2 genotypes were determined. We also correlated ADH2, ADH3, and ALDH2 genotypes with drinking behavior in 100 Chinese men. We discovered that ADH2*2 and ADH3*1, alleles that encode the high activity forms of alcohol dehydrogenase, as well as the mutant ALDH2*2 allele were less frequent in alcoholics than in controls. The presence of ALDH2*2 was associated with slower alcohol metabolism and the most intense flushing. In those homozygous for ALDH2*1, the presence of two ADH2*2 alleles correlated with slightly faster alcohol metabolism and more intense flushing, although a great deal of variability in the latter was noted.

Alcohol Dehydrogenase↗

PubMed1993

Selective breeding for alcohol preference and associated responses.

Selective breeding for high and low alcohol-drinking preference has produced rat lines useful for studying the nature of excessive alcohol-seeking behavior. Compared with the alcohol-nonpreferring line, the preferring animals exhibit heightened responsivity to the low-dose activating effects of ethanol as well as enhanced capacity for developing tolerance to the aversive, behaviorally impairing effects of ethanol. The preferring animals exhibit lower brain serotonin and dopamine neurotransmitter activity as well as differences in other neurotransmitter neuromodulator systems, compared with the alcohol-nonpreferring animals.

Alcohol Drinking↗