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Query: UNIPROT:P06889 (Mol)
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Ammonia clearance, portal blood ammonia, and amino acid concentrations were studied during induction of cirrhosis by carbon tetrachloride in rats. Exposure to CCl4 vapors twice weekly for 7-16 weeks doubled orotic acid excretion. If exposure was discontinued for 7 days, the orotic acid excretion decreased despite the presence of cirrhosis proven histologically. Replacement of dietary casein with soybean protein eliminated the CCl4-induced orotic aciduria in growing rats but not in adults. Supplementation of casein with 1.5% arginine did not prevent CCl4-induced orotic aciduria. [14C]Orotate uptake into RNA and DNA of liver was not impaired. Perfusion of livers of cirrhotic animals with ammonia concentrations between 0.2 and 3.0 mM revealed no significant decreases in urea synthesis rates due to cirrhosis and no increase in the tendency to make orotic acid at a given ammonia concentration. However, ammonia uptake by cirrhotic livers was significantly reduced, resulting in higher ammonia concentrations in the effluent when there was moderate-to-severe cirrhosis. Portal blood samples taken from rats exposed to CCl4 had higher ammonia concentrations as cirrhosis worsened. The results lend support to the "intact hepatocyte" hypothesis of cirrhosis which attributes metabolic abnormalities to intrahepatic shunts.
Exp Mol Pathol 1989 Jun
PMID:Orotic acid overproduction in experimental cirrhosis of rats. 272 54

Endothelial fenestrae in the microcirculatory walls of fetal (18th and 21st days), newborn (1st and 5th days), and adult rat livers have been studied by an interactive analysis of scanning electron microscope images. Our results show that liver endothelial cells contain different fenestration patterns depending on both their specific location in the liver acinus and the developing period. Portal vessels have a continuous endothelium in both fetal and postnatal livers as in the adult liver. Endothelial cells in central veins change from highly fenestrated in the fetal and neonatal livers to continuous in the adult liver. The number of fenestrae per square micrometer of endothelium is similar along the sinusoidal network of fetal liver, but increases in the zone 3 sinusoids of newborn liver through the adult liver, where it has tripled the number in the zone 1 sinusoids. Porosity values in sinusoidal endothelium progressively decrease in the fetal to postnatal transition due to the disappearance of large fenestrae (greater than 250 nm) which accompanies the residual hemopoietic activity. While we do not known which factors specifically regulate these fenestration patterns, their configuration in fetal liver, before hepatic tissue has assumed its heterogeneous functioning postnatally, is worthy of note.
J Ultrastruct Mol Struct Res
PMID:Structural changes in endothelial cells of developing rat liver in the transition from fetal to postnatal life. 345 69

Neuroblastoma cells clone N-2a, differentiated by serum deprivation, were found to take up tritiated serotonin ([3H]5-HT) from the external medium by means of a saturable mechanism which follows Michaelis-Menten kinetics. The apparent Km of uptake was 1.27 microM and the Vmax 720 fmoles/min/10(6) cells. The uptake was temperature-dependent and partially sodium-dependent, and was inhibited by ouabain and by selected metabolic inhibitors (sodium azide, 2,4-dinitrophenol, and iodoacetamide). Fluoxetine and desmethylimipramine (DMI) were equally effective inhibitors of [3H]5-HT uptake (IC50 = 13.7 microM and 13.6 microM). The uptake was structurally specific, since unlabeled 5-HT was a better inhibitor of [3H]5-HT uptake than norepinephrine (NE) (IC 50 = 0.6 microM and 9.4 microM). The neurotoxins 6-hydroxydopamine and 5,6-dihydroxytryptamine were cytotoxic to differentiated N-2a cells, causing time- and concentration-dependent inhibition of [3H]thymidine incorporation into DNA, 5,7-Dihydroxytryptamine had little cytotoxic effect. Non-differentiated N-2a cells, supplemented with 5% fetal calf serum, were also found to take up [3H]5-HT by a concentration-, temperature-, and energy-dependent process. The apparent Km of uptake was 0.96 microM and the Vmax was 619 fmoles/min/10(6) cells. However, in nondifferentiated cells [3H]5-HT uptake was not sodium-dependent, not inhibited by ouabain, less effectively inhibited by fluoxetine and DMI (IC50 = 148 microM and 107 microM), and not selectively inhibited by unlabeled 5-HT as compared with NE (IC50 = 7.9 microM and 6.0 microM).
Mol Pharmacol 1982 Mar
PMID:Characterization of serotonin uptake in cultured neuroblastoma cells. Difference between differentiated and nondifferentiated cells. 709 39

The serotonergic regulation of neuropeptide and glutamic acid decarboxylase (GAD) mRNA level in the rat basal ganglia was investigated by determining the effects of chronic treatment with the serotonin uptake blocker fluoxetine and the serotonin 5-HT2 agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrobromide (DOI). Fluoxetine (10 mg/kg) induced a reduction of preproenkephalin and GAD65 mRNA levels in the caudate-putamen and nucleus accumbens core and shell after 5 days of treatment. In addition, GAD65 mRNA levels were reduced in the globus pallidus. These changes appeared to be transient as they were not found after 15 days of fluoxetine treatment. DOI (7 mg/kg), administered for 9 days, induced a decrease of preprodynorphin mRNA levels in the caudate-putamen and the nucleus accumbens core and shell. No regional differentiation in the effects of fluoxetine and DOI was observed. Based on the present results, we propose that an increased 5-HT tone may reduce enkephalin and GABA mRNA levels in striatal regions and in the globus pallidus. Our results further show that preproenkephalin mRNA is not affected by chronic 5-HT2 receptor stimulation, indicating that the fluoxetine-induced decrease in preproenkephalin mRNA levels involves other 5-HT receptors than the 5-HT2 receptor. Preprodynorphin mRNA levels, on the other hand, were found to be reduced after chronic 5-HT2 receptors than stimulation. This observation, together with our previous finding that the 5-HT2 antagonist ritanserin tends to increase preprodynorphin mRNA levels, suggests a 5-HT2-mediated tonic inhibition of preprodynorphin mRNA levels.
Brain Res Mol Brain Res 1998 Feb
PMID:Serotonergic regulation of neuropeptide and glutamic acid decarboxylase mRNA levels in the rat striatum and globus pallidus: studies with fluoxetine and DOI. 952 47

Obsessive compulsive disorder (OCD) is characterized by recurrent and intrusive thoughts that are distressing (obsessions) and/or repetitive behaviors or mental acts that the person feels driven to perform (compulsions). OCD has a partly genetic basis. For treatment of OCD, potent serotonin reuptake inhibitor (SRI) drugs (clomipramine (Anafranil), fluvoxamine (Luvox), fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil)), which act on the serotonin transporter protein, are uniquely efficacious. A polymorphism in the promoter region of the gene (SLC6A4) encoding this protein, was recently reported to affect protein expression and to be associated with measures of anxiety and depression and with autism (using a family-controlled transmission disequilibrium test (TDT) design). SLC6A4 therefore has strong a priori support for potentially influencing risk for OCD: the protein it encodes is a medication target; a polymorphism in the gene affects function; and that polymorphism has been shown to be associated with behavioral phenotypes. We used the TDT with a set of 34 European-American family trios, 30 unrelated and four drawn from an extended pedigree, to test for linkage disequilibrium between OCD and alleles at the SLC6A4 promoter polymorphic locus. Of 35 heterozygous parents, 24 transmitted the 'l' SLC6A4 allele and 11 transmitted the 's' allele (chi 2 TDT = 4.83; P < 0.03). Considering only the 13 SRI drug nonresponders, there were 13 heterozygous parents, of whom 10 transmitted the 'l' allele and three the 's' allele (chi 2 TDT = 3.77; P < 0.052). These data provide preliminary support for association and linkage disequilibrium between the SLC6A4 'l' allele and OCD.
Mol Psychiatry 1998 May
PMID:Evidence for linkage disequilibrium between serotonin transporter protein gene (SLC6A4) and obsessive compulsive disorder. 967 4

Fluoxetine is used in the treatment of a variety of clinical disorders including depression and obesity, and of cocaine detoxification or alcoholism. It is generally believed that fluoxetine exerts its clinical effects because it selectively blocks 5-hydroxytryptamine (5HT) reuptake into nerve terminals. In here we describe that fluoxetine antagonized the neuronal homomeric alpha 7 nicotinic acetylcholine receptors (nAChR) expressed in Xenopus oocytes, with an IC50 of 43 microM, when fluoxetine was coapplied with ACh, and of 1.6 microM when the oocytes were pretreated briefly with fluoxetine. A similar block occurred in oocytes expressing L247T alpha 7 mutant nAChR. Furthermore, blockage of mutant alpha 7 receptors appeared non-competitive and was stronger with cell membrane hyperpolarization. Cell-attached single channel recordings in oocytes expressing L247T alpha 7 mutant nAChR showed that the voltage-dependence of the blockage by fluoxetine could be due to a drastic decrease in channel opening frequency accompanied by marked channel flickering and reduced channel conductance. We conclude that fluoxetine behaves as a reversible blocker of both wild and mutant alpha 7 receptors; and that the Leu-247T mutation in the channel domain renders the blockage of alpha 7 nAChR by fluoxetine voltage-dependent. These effects of fluoxetine on alpha 7 receptors may be clinically important.
Mol Psychiatry 1998 Jul
PMID:Effects of fluoxetine on wild and mutant neuronal alpha 7 nicotinic receptors. 970 46

1. The present survey compares the effects of antidepressants and their principal metabolites on reuptake of biogenic amines and on receptor binding. The following antide-pressants were included in the study: the tricyclic antidepressants amitriptyline, dothiepin, and lofepramine and the atypical antidepressant bupropion, which all have considerable market shares in the UK and/or US markets; the selective serotonin reuptake inhibitors (SSRIs) citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline; and the recently approved antidepressants venlafaxine and nefazodone. 2. Amitriptyline has similar in vitro reuptake inhibitory potencies for 5-HT and NA, whereas the metabolite nortriptyline is preferentially a NA reuptake inhibitor. Both amitriptyline and nortriptyline are also 5-HT2 receptor antagonists. 3. Dothiepin has equipotent 5-HT and NA reuptake inhibitory activity, whereas northiaden shows a slight selectivity for NA reuptake inhibition. Dothiepin and northiaden are also 5-HT2 receptor antagonists. The slow elimination rate of northiaden (36-46 hr) compared to dothiepin (14-24 hr) suggests that northiaden contributes significantly to the therapeutic effect of dothiepin. 4. Lofepramine is extensively metabolized to desipramine. Desipramine plays an important role in the antidepressant activity of lofepramine, as the plasma elimination half-life of lofepramine (4-6 hr) is much shorter than that of desipramine (24 hr). Both compounds are potent and selective inhibitors of NA reuptake. 5. The five approved SSRIs, citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline, are potent 5-HT reuptake inhibitors, and the demethyl metabolites, norfluoxetine, demethylsertraline, and demethylcitalopram, also show selectivity. Paroxetine and sertraline are the most potent inhibitors of 5-HT reuptake, whereas citalopram is the most selective. Fluoxetine is the least selective and the metabolite of fluoxetine, norfluoxetine, is a more selective and more potent 5-HT reuptake inhibitor than the parent compound and has an extremely long half-life (7-15 compared to 1-3 days). Thus the metabolite plays an important role for the therapeutic effect of fluoxetine. Fluoxetine is also a 5-HT2C receptor antagonist. Demethylsertraline is a weaker and less selective 5-HT reuptake inhibitor in vitro than sertraline, but demethylsertraline has a very long half-life (62-104 hr) compared to the parent compound (24 hr) and it might play a role in the therapeutic effects of sertraline. Demethylcitalopram has about a 10 times lower 5-HT reuptake inhibitory potency in vitro than citalopram, and the elimination half-lives are approximately 1.5 and 2 days, respectively. 6. Bupropion and hydroxybupropion are weak inhibitors of biogenic amine reuptake. The mechanisms of action responsible for the clinical effects of bupropion are not fully understood, but it has been suggested that both dopaminergic and noradrenergic components play a role and that the hydroxybupropion metabolite contributes significantly to the antidepressant activity. 7. Venlafaxine and O-demethylvenlafaxine are weak inhibitors of 5-HT and NA reuptake, and the selectivity ratios are close to one. O-Demethylvenlafaxine is eliminated more slowly than venlafaxine (plasma half-lives of 5 and 11 hr, respectively), and it is likely that it contributes to the overall therapeutic effect of venlafaxin. 8. Nefazodone and alpha-hydroxynefazodone are equipotent 5-HT and NA reuptake inhibitors. Both compounds are also 5-HT2 receptor antagonists. Both parent compound and metabolite have short elimination half-lives.
Cell Mol Neurobiol 1999 Aug
PMID:Comparison of the effects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding. 1037 21

Fluoxetine (Prozac) is an antidepressant that is thought to act by blocking presynaptic reuptake of the neurotransmitter serotonin. Despite widespread clinical use of fluoxetine, direct evidence for this mechanism has been difficult to obtain in vivo. We have determined that fluoxetine has an additional neuromuscular effect on C. elegans that is distinct from inhibition of serotonin reuptake. By screening for mutants resistant to this effect, we have identified seven genes. We report that two of these genes are homologous to each other and define a novel gene family that encodes over a dozen multipass transmembrane proteins. Our findings may have clinical implications for the mechanism of action of fluoxetine.
Mol Cell 1999 Aug
PMID:Fluoxetine-resistant mutants in C. elegans define a novel family of transmembrane proteins. 1048 30

The effects of fluoxetine on the oxidative phosphorylation of mitochondria isolated from rat brain and on the kinetic properties of submitochondrial particle F1F0-ATPase were evaluated. The state 3 respiration rate supported by pyruvate + malate, succinate, or ascorbate + tetramethyl-p-phenylenediamine (TMPD) was substantially decreased by fluoxetine. The IC50 for pyruvate + malate oxidation was approximately 0.15 mM and the pattern of inhibition was the typical one of the electron-transport inhibitors, in that the drug inhibited both ADP- and carbonyl cyanide m-chlorophenylhydrazone (CCCP)-stimulated respirations and the former inhibition was not released by the uncoupler. Fluoxetine also decreased the activity of submitochondrial particle F1F0-ATPase (IC50 approximately 0.08 mM) even though K0.5 and activity of Triton X-100 solubilized enzyme were not changed substantially. As a consequence of these effects, fluoxetine decreased the rate of ATP synthesis and depressed the phosphorylation potential of mitochondria. Incubation of mitochondria or submitochondrial particles with fluoxetine under the conditions of respiration or F1F0-ATPase assays, respectively, caused a dose-dependent enhancement of 1-anilino-8-naphthalene sulfonate (ANS) fluorescence. These results show that fluoxetine indirectly and nonspecifically affects electron transport and F1F0)-ATPase activity inhibiting oxidative phosphorylation in isolated rat brain mitochondria. They suggest, in addition, that these effects are mediated by the drug interference with the physical state of lipid bilayer of inner mitochondrial membrane.
Mol Cell Biochem 1999 Sep
PMID:Fluoxetine interacts with the lipid bilayer of the inner membrane in isolated rat brain mitochondria, inhibiting electron transport and F1F0-ATPase activity. 1054 58

Portal vein branch embolization is often performed before hepatectomy to prevent postoperative liver failure. It is, however, still not clear how the embolized lobe shrinks and the non-embolized lobe proliferates in counterbalance. We investigated the expression of positive and negative regulators of hepatocyte growth to clarify the mechanisms of liver growth and atrophy in a rat portal vein ligation (PVL) model compared with partial hepatectomy (PH). A significant increase in DNA synthesis within the non-ligated lobe reached a peak at 36 h, a delay of 12 h as compared with PH, while no increase occurred in the ligated lobe. Expression of hepatocyte growth factor mRNA remarkably increased in the non-ligated growing lobe between 6 and 24 h, but was only slightly elevated in the ligated shrinking lobe. Contrarily, negative regulators of hepatocyte proliferation, such as TGF-beta1 and IL-1beta, were strongly expressed in the ligated shrinking lobe. Thus, the changes of portal venous flow and/or pressure caused by PVL may contribute to induction of different kinds of growth factors between the ischemic and non-ischemic lobes; these factors possibly regulate liver regeneration and atrophy after PVL.
Int J Mol Med 2000 Feb
PMID:Different expression of positive and negative regulators of hepatocyte growth in growing and shrinking hepatic lobes after portal vein branch ligation in rats. 1063 97


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