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PubMed2005

Identification of the first pyrimidine nucleobase transporter in Leishmania: similarities with the Trypanosoma brucei U1 transporter and antileishmanial activity of uracil analogues.

While purine transport has been widely studied in protozoa, almost nothing is known about their capacity to salvage pyrimidines. Here, we report a Leishmania major transporter with high affinity for uracil (Km=0.32+/-0.07 microM) which we designated LmU1. This transporter displayed a high degree of specificity, as it had virtually no affinity for cytosine, thymine or purine nucleobases, nor did it transport pyrimidine nucleosides. Highest affinity was for 5-fluorouracil. The results show that the permeant binding site of LmU1 interacts strongly with the keto groups of uracil, as shown by a low affinity for 2-thio- and 4-thiouracil. LmU1 appears to further bind uracil through a weak hydrogen bond with N(1)H of the pyrimidine ring in addition to a stronger H-bond with N(3)H. Substrate binding and selectivity were strikingly similar to that of the U1 transporter in the related kinetoplastid Trypanosoma brucei. Uracil analogues likely to be transported by LmU1 were also screened for antileishmanial activity, with 5-fluorouracil displaying strong activity against promastigotes and intracellular amastigotes. Overall, the results show that, like purine nucleobase transport, pyrimidine nucleobase transport function is very similar in L. major and T. brucei insect forms.

Animals↗
PubMed1988

Purification and properties of mitochondrial uracil-DNA glycosylase from rat liver.

Uracil-DNA glycosylase from rat liver mitochondria, an inner membrane protein, has been purified approximately 575,000-fold to apparent homogeneity. During purification two distinct activity peaks, designated form I and form II, were resolved by phosphocellulose chromatography. Form I constituted approximately 85% while form II was approximately 15% of the total activity; no interconversion between the forms was observed. The major form was purified as a basic protein with an isoelectric point of 10.3. This enzyme consists of a single polypeptide with an apparent Mr of 24,000 as determined by recovering glycosylase activity from a sodium dodecyl sulfate-polyacrylamide gel. A native Mr of 29,000 was determined by glycerol gradient sedimentation. The purified enzyme had no detectable exonuclease, apurinic/apyrimidinic endonuclease, DNA polymerase, or hydroxymethyluracil-DNA glycosylase activity. A 2-fold preference for single-stranded uracil-DNA over a duplex substrate was observed. The apparent Km for uracil residues in DNA was 1.1 microM, and the turnover number is about 1000 uracil residues released per minute. Both free uracil and apyrimidinic sites inhibited glycosylase activity with Ki values of approximately 600 microM and 1.2 microM, respectively. Other uracil analogues including 5-(hydroxymethyl)uracil, 5-fluorouracil, 5-aminouracil, 6-azauracil, and 2-thiouracil or analogues of apyrimidinic sites such as deoxyribose and deoxyribose 5'-phosphate did not inhibit activity. Both form I and form II had virtually identical kinetic properties, and the catalytic fingerprints (specificity for uracil residues located in a defined nucleotide sequence) obtained on a 152-nucleotide restriction fragment of M13mp2 uracil-DNA were almost identical. These properties differentiated the mitochondrial enzyme from that of the uracil-DNA glycosylase purified from nuclei of the same source.

Animals↗
PubMed1975

1H nuclear magnetic resonance of modified bases of valine transfer ribonucleic acid (Escherichia coli). A direct monitor of sequential thermal unfolding.

Proton magnetic resonances at 220 MHz from three nucleotide residues of valine I tRNA (Escherichia coli) serve as intrinsic probes of local molecular structure. Resonances from the methyl group of ribothymidine, the methyl group of N6-methyladenosine, and the C-5 methylene of dihydrouridine monitor separate conformational transitions in the TpsiC, anticodon, and dihydrouridine loops, respectively. As the temperature is raised in a solution containing 0.23 M Na+ and no Mg2+, the dihydrouridine region melts with a Tm of 55 degrees, the anticodon region at 58 degrees, and the TpsiC region at 67 degrees. The dihydrouridine nuclear magnetic resonance (NMR) transition correlates with the major change in absorbance monitored in the uv at 330 nm which is ascribed to structural pertubations near the 4-thiouracil moiety. On the NMR time scale slow exchange is seen throughout the temperature range for dihydrouridine and below the apparent Tm for the ribothymidine methyl group. Chemical shift and line width differences between folded and unfolded forms of the polynucleotide indicate that, in the native structure, ribothymidine is in a highly structured region and N6-methyladenosine is in a somewhat less restricted environment. Narrow line widths for the C-5 methylene triplet are found over the whole temperature range indicating that this base is undergoing rapid internal reorientation relative to the overall macromolecule.

Adenosine↗
PubMed1996

RNA conformation in the Tat-TAR complex determined by site-specific photo-cross-linking.

Transcriptional regulation in human immunodeficiency virus type 1 (HIV-1) requires specific interactions of Tat protein with the transactivation responsive region (TAR) RNA, a 59-base stem-loop structure located at the 5'-end of all mRNAs. We have used a site-specific cross-linking method based on 4-thiouracil (4-thioU) photochemistry to determine the conformation of TAR RNA and its interaction with Tat protein under physiological conditions. Three different TAR RNA constructs with a single 4-thioU residue at position 23, 38, or 40 were synthesized. Upon UV irradiation, 4-thioU at all three positions formed interstrand covalent cross-links in TAR RNA. Determination of cross-link sites by RNA sequencing revealed that 4-thioU at position 23 makes a direct contact with U40, while a 4-thoU at position 40 cross-links to C24 and C25, and at position 38, 4-thioU contacts G26 in TAR RNA. The addition of arginine did not alter the yield or the site of RNA-RNA cross-link. However, in the presence of Tat(38-72), UV irradiation of RNA modified with 4-thioU at position 23 or 38 resulted in RNA- protein cross-links, but no RNA-RNA cross-links were observed. 4-thioU at position 40 formed both RNA-RNA and RNA-protein cross-links in the presence of Tat(38-72). An intriguing finding of our studies was that a cross-linked TAR RNA with 4-thioU at position 40 retained specific Tat-binding activity. Our results establish four important conclusions about Tat-TAR structure. (1) U23 of free TAR RNA is in close contact with U40. (2) U40 is in close proximity to C24 and C25 both in free TAR RNA and in a complex with Tat. (3) Tat protein directly contacts U23, U38, and U40 in the major groove of TAR RNA. (4) Tat protein can recognize a TAR RNA structure containing an interrupted bulge which is formed by a covalent link between U40 and two bulge residues, C24 and C25. These structural studies provide new insights into tertiary folding of TAR RNA and its interaction with Tat protein.

Base Sequence↗
PubMed1996

(1,3-Dimethyluracil-5-yl)mercury(II): Preparative, Structural, and NMR Spectroscopic Studies of an Analog of CH(3)Hg(II).

The solution behavior of (1,3-DimeU-C5)Hg(CH(3)COO) (1a) (1,3-DimeU = 1,3-dimethyluracil) with regard to acetate replacement by anions X (Cl(-), Br(-), I(-), NO(3)(-), SCN(-), CN(-)) and by other model nucleobases (1-methylcytosine, 1-MeC, 1-methyluracil, 1-MeUH, 1-methylthymine, 1-MeTH, 9-ethylguanine, 9-EtGH, and 2-thiouracil, 2-ThioUH) has been studied, primarily by means of (1)H and (199)Hg NMR spectroscopy. Moreover, the bis(1,3-DimeU-C5) complex of Hg has been crystallized and studied by X-ray crystallography. 7a: orthorhombic system, space group Fdd2, a = 14.185(4) Å, b = 25.275(7) Å, c = 7.924(2) Å, V = 2840(2) Å(3), Z = 8. The acetato ligand of 1a is readily displaced by anions X, frequently followed by disproportionation reactions leading to HgX(2) and 7a. The donor atom X trans to C(5) has an effect on (3)J coupling between (199)Hg and H(6) of the 1,3-DimeU ligand according to NO(3)(-) > OAc(-) > Cl(-) approximately Br(-) > I(-) > SCN(-) > CN(-) > 1,3-DimeU-C5 with extremes being 222 (X = NO(3)(-)) and 107 Hz (7a). In the presence of excess metal ions (Ag(+), Hg(2+)), 1a forms hetero- and homonuclear derivatives with the second metal ion probably sitting at O(4). The mixed nucleobase complexes have the second base bound to Hg via N(3) (1-MeU (2a), 1-MeT (3a)), N(4) (1-MeC(-) (4a), 1-MeC (4b)), N(1) (9-EtG (5a)), N(7) (9-EtGH (5b)), and N(1), N(7) (9-EtG (5c)), as well as S(2) (2-ThioU (6a)). With the exception of the 9-ethylguanine complexes 5b and 5c, all the other complexes are inert on the (1)H time scale. In several cases, e.g. 2a, 3a, 4a, and 5a, formation of dinuclear Hg or heteronuclear Ag and Pt derivatives has been established by multinuclear NMR spectroscopy.

Journal Article↗
PubMed2000

Antioxidant activity and radioprotective effects against chromosomal damage induced in vivo by X-rays of flavan-3-ols (Procyanidins) from grape seeds (Vitis vinifera): comparative study versus other phenolic and organic compounds.

The quantitative distribution of several flavan-3-ols was determined using HPLC in a grape (Vitis vinifera) seed extract (GSE) of four cultivars grown in the region of Murcia. Polymer >/= C(4) units made up the largest group of procyanidins in the GSE (90.92%, expressed as HPLC % area). The antioxidant activity of GSE and other reference compounds was investigated by measuring their ability to scavenge the ABTS(*)(+) radical cation (TEAC). The most effective compounds were, in order: GSE > rutin > (+)-catechin > diosmin >/= ascorbic acid. The radioprotective effects of GSE and other reference compounds were determined by using the micronucleus test for anticlastogenic activity, any reduction of the frequency of micronucleated polychromatic erythrocytes (MnPCEs) being evaluated in the bone marrow of mouse exposed to X-rays. The most effective compounds were, in order: GSE > rutin > dimethyl sulfoxide (DMSO) > ascorbic acid > 6-n-propyl-2-thiouracil-6c (PTU) > diosmin. The higher ABTS(*)(+) scavenging capacity and anticlastogenic activity of GSE can be explained, structurally, by the high number of conjugated structures between the catechol groups in the B-rings and the 3-OH free groups of the polymeric polyphenolic skeleton and, in addition, by the stability of the aroxyl flavonoid radical generated in the above processes.

Animals↗
PubMed1995

Synthesis and antiviral activity of 6-benzyl analogs of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) as potent and selective anti-HIV-1 agents.

Several 6-benzyl analogs of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (1; HEPT) were synthesized and evaluated for their anti-HIV-1 activity. LDA (lithium diisopropylamide) lithiation of 5-ethyluracil derivatives 7 and 8 and subsequent reaction with an aryl aldehyde gave 6-(arylhydroxymethyl)-5-ethyluracil derivatives 9-12. 6-(Arylhydroxymethyl)-5-isopropyluracil derivatives 15-18 were prepared from the 5-isopropyl-2-thiouracil derivatives 13 and 14 by the above procedure following oxidative hydrolysis of the thione. Preparation of the target 5-alkyl-1-(alkoxymethyl)-6-benzyluracil derivatives 27-34 was carried out by acetylation of 9-14 followed by Pd-catalyzed hydrogenolysis. The 1-butyl- (37 and 39) and 1-(2-methoxyl)- (38 and 40) 5-alkyl-6-benzyluracils were synthesized by 1-alkylation of the 3-phenacyl derivatives 35 and 36 with alkyl halides followed by deprotection of the 3-phenacyl group. Compounds synthesized in this study inhibited HIV-1 replication in MT-4 cells in the submicromolar to namomolar concentration range. From this series of compounds, 6-benzyl-1-(ethoxymethyl)-5-isopropyluracil (33) was selected for clinical evaluation.

Animals↗
PubMed2005

Parallel solution-phase and microwave-assisted synthesis of new S-DABO derivatives endowed with subnanomolar anti-HIV-1 activity.

A simple and efficient methodology for the parallel solution-phase synthesis has been set up to obtain a series of thiouracils, in turn selectively S-benzylated under microwave irradiation to give new S-DABOs. Biological screening led to the identification of compounds with nanomolar activity toward both the highly purified recombinant human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) enzyme (wild-type and mutants) and wild-type (wt) and mutant HIV-1 strains. In particular, 20 was found to be the most potent S-DABO reported so far (ID50 = 26 nM toward the isolated wt enzyme) with subnanomolar activity toward both the wt and the pluriresistant virus (IRLL98) HIV-1 strain (EC50 < 0.14 nM and EC50 = 0.22 nM, respectively). Molecular modeling calculations were also performed to investigate the binding mode of such compounds onto the non-nucleoside reverse transcriptase inhibitor binding site and to rationalize the relationships between their chemical structure and activity values toward wt RT.

Anti-HIV Agents↗
PubMed1998

Synthesis and anti-HIV-1 activity of novel 2,3-dihydro-7H-thiazolo[3,2-a]pyrimidin-7-ones.

Appropriately substituted 2,3-dihydro-7H-thiazolo[3,2-a]pyrimidin-7-ones 9-12 and 18 were considered as annulated analogues of HEPT (1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-thymine), and some of these compounds were also found active against HIV-1, the most active one being 2,3-dihydro-5-[(3,5-dimethylphenyl)methyl]-3-ethoxy-6-ethyl-7H- thiazolo[3,2-a]pyrimidin-7-one (10b). S-Alkylation of 5-alkyl-6-(arylmethyl)-2-thiouracils 1-4 was performed with 2-bromoacetaldehyde acetals to furnish the S-[bis(alkoxy)ethyl] derivatives 5-8 and with allyl bromide to furnish S-allyl derivatives 17. The target compounds 9-12 were obtained by an N1 regioselective intramolecular cyclization reaction of silylated 5-8 using trimethylsilyl trifluoromethanesulfonate (TMS triflate) as the catalyst. Treatment of the S-allyl derivatives 17 with bromine in dry methylene chloride afforded the 3-(bromomethyl) derivatives 18.

Alkylation↗
PubMed2002

Solid-phase synthesis of 4(1H)-quinolone and pyrimidine derivatives based on a new scaffold-polymer-bound cyclic malonic acid ester.

An efficient method for the preparation of polymer-bound cyclic malonic acid ester starting from Merrifield resin has been developed. Reaction of the resin-bound cyclic malonic acid ester with triethyl orthoformate and subsequent double substitution with nucleophilic reagents, such as arylamine, urea, thiourea, 2-aminobenzothiazoles, or isothiosemicarbazones, afforded the corresponding polymer-bound substituted aminomethylene cyclic malonic acid esters, which upon thermal treament led to 4(1H)-quinolones, 3-substituted uracils and thiouracils, 4H-pyrimido[2,1-b]benzothiazol-4-ones, and 1-(N-alkylidene or benzylideneamino)-1,6-dihydro-2-methylthio-6-oxo-pyrimidines, depending on the structures of the nucleophilic reagents.

Journal Article↗
PubMed2005

Generation of thiyl radicals by the photolysis of 5-iodo-4-thiouridine.

The photochemistry of 2',3',5'-tri-O-acetyl-5-iodo-4-thiouridine (3) in deoxygenated 1:1 CH(3)CN-H(2)O pH 5.8 (phosphate buffer) solution has been studied by means of steady-state and nanosecond laser flash photolysis methods. Under steady-state irradiation (lambda > or = 334 nm), the stable photoproducts were iodide ion, 2',3',5'-tri-O-acetyl-4-thiouridine (4), and two disulfides. The disulfides were the symmetrical bis-(2',3',5'-tri-O-acetyl-5-iodo-4-thiouridine) (5) and unsymmetrical 6, which contains both 4-thiouridine and 5-iodo-4-thiouridine residues. The formation of the dehalogenated photoproduct suggests that C(5)-I bond cleavage is a primary photochemical step. Attempts to scavenge the resulting C(5)-centered radical by suitable addends, bis-(N-alpha-acetyl)cystine-bis-N-ethylamide or benzene, were unsuccessful. Analysis of the photoproducts formed under these conditions showed that the S-atom is the reactive center. The photoproduct 4, obtained by irradiation of 3 in CD(3)CN-H(2)O, followed by reversed-phase HPLC isolation using nonlabeled eluents, did not contain deuterium. An analogous experiment performed in CH(3)CN-D(2)O gave deuterated product 4-d with 88% of the deuterium incorporated at C(5). Transient absorption observed upon laser excitation (lambda= 308 nm) of 3 was assigned to the 4-uridinylthiyl radical on the basis of the similarity of this spectrum with that obtained upon laser photolysis of the disulfide: bis-(2',3',5'-tri-O-acetyl-4-thiouridine) 14. On the basis of the results of steady-state and laser photolysis studies, a mechanism of the photochemical reaction of 3 is proposed. The key mechanistic step is a transformation of the C(5)-centered radical formed initially by C(5)-I bond cleavage into a long-lived S-centered radical via a 1,3-hydrogen shift. Theoretical calculations confirmed that the long-lived S-centered radical is the most stable radical derived from the 4-thiouracil residue.

Affinity Labels↗
PubMed2004

A versatile synthesis of fluorinated uracils in solution and on solid-phase.

[reaction: see text] An efficient and convenient two-step synthesis of new fluorinated uracils is described. The first step involves the condensation of an ester enolate with a fluorinated nitrile to furnish fluorinated beta-enamino esters. In turn, these compounds react with organic isocyanates or isothiocyanates to give C-6 fluorinated uracils or thiouracils, respectively, in excellent yields. This synthesis has been successfully adapted to solid-phase conditions with high diversity, thereby facilitating the creation of small (thio)uracil libraries.

Hydrocarbons, Fluorinated↗
PubMed1997

In vitro metabolism of N-(5-chloro-2-methylphenyl)-N'-(2-methylpropyl)thiourea: species comparison and identification of a novel thiocarbamide-glutathione adduct.

The in vitro metabolism of SDZ HDL 376, a thiocarbamide developed for the treatment of atherosclerosis, was investigated in rat, dog, monkey, and human liver microsomes, as well as in rat and human liver slices. [14C]SDZ HDL 376 was extensively metabolized in all the species except human. In rat liver microsomes an S-oxide was the major metabolite. In human and monkey microsomes, carbon hydroxylation was favored. The NADPH-dependent oxidation of SDZ HDL 376 resulted in covalent binding to microsomal protein. Addition of GSH to the incubations decreased protein binding in a concentration-dependent manner and resulted in a novel SDZ HDL 376-GSH adduct. Adduct formation required NADPH and was mediated predominantly by cytochrome P450. Inhibition of cytochrome P450 by 1-aminobenzotriazole resulted in a 95% decrease in adduct formation, while heat inactivation of flavin-containing monooxygenases resulted in a 10% decrease. Unlike other thiocarbamides which form disulfide adducts with GSH, the SDZ HDL 376 adduct contained a thioether linkage as characterized by LC/MS/MS and reference to a synthetic standard. Reactions performed with [35S]GSH resulted in a [35S]SDZ HDL 376-GSH adduct, demonstrating the sulfur was derived from GSH. Adduct formation was faster in rat microsomal reactions compared to human microsomes. Other structurally unrelated thiocarbamides (phenylthiourea, methimazole, 2-mercaptobenzimidazole, 2-mercaptoquinazoline, and 2-propyl-6-thiouracil) did not form similar adducts in rat liver microsomes supplemented with GSH. Therefore, the GSH adduct of SDZ HDL 376 is unique for this type of thiocarbamide. These results suggest that the bioactivation and detoxification of SDZ HDL 376 differ significantly from other thiocarbamides. Furthermore, the in vitro formation of S-oxides and GSH adducts in rat hepatic tissue, and ring hydroxylation and glucuronidation in human hepatic tissue, suggests rats may be more susceptible to the toxicity of SDZ HDL 376 compared to humans.

Animals↗
PubMed2002

Modulation of cardiac A1-adenosine receptors in rats following treatment with agents affecting heart rate.

Effects of chronic treatment affecting heart rate on A1 adenosine receptor levels and their functions were studied. Treatment of rats with isoproterenol for 10 days accelerated heart rate and increased the level of adenosine receptors, in both the atria and ventricles. Negative dromotropic response of isolated heart to adenosine was enhanced in isoproterenol-treated rats. Similar results were obtained following treatment with atropine sulfate, or swimming training but not after treatment with thyroxine. On the other hand, treatment with amiodarone, which normally causes a decrease in heart rate, also increased the level of adenosine receptors in both atria and ventricles. The sensitivity of the isolated heart to the negative dromotropic and chronotropic effects of adenosine was not enhanced in the amiodarone treated rats. Similar results were obtained following treatment with propranolol, while treatment with PTU (6-n-propyl-2-thiouracil) increased adenosine sensitivity in the isolated heart. It was concluded that the levels of A1 adenosine receptors in the heart correspond to heart rate, and to cardiac efficiency. While an increase in heart rate was followed by up-regulation of A1 adenosine receptors, a decrease in heart rate caused a moderate elevation of these receptors.

Adenosine↗
PubMed2003

Effect of hypo- and hyperthyroid states on phospholipid composition in developing rat heart.

The aim of this study was to examine the effect of hypo- and hyperthyroidism on the phospholipid composition in developing rat heart. The hypothyroid state (PTU) was induced by 0.05% 6-n-propyl-2-thiouracil in drinking water given to nursing mothers from the postnatal day 2-21. The hyperthyroidism (T3) was made by daily injection of 3,3',5-triiodo-L-thyronine (10 microg/100 g body wt) to newborns in the same time period. Age matched intact littermates were taken as euthyroid controls. PTU decreased the concentration of total phospholipids (PL), choline phosphoglycerides (PC), ethanolamine phosphoglycerides (PE) and diphosphatidylglycerol (DPG) and increased the proportion of plasmalogen component of PE (PLPE). T3 increased the concentration of PL, PC, PE, DPG and decreased PLPE in comparison with euthyroid controls. The ratio of saturated/unsaturated fatty acids (FA) in PE was decreased in PTU and increased in T3 group. The ratio of n-6/n-3 polyunsaturated FA in PC, PE and phosphatidylinositol (PI) was increased in PTU due to increase of 18:2n-6 and decrease of 22:6n-3 proportion. T3 decreased this ratio because of decline in 20:4n-6 and rise in 22:6n-3 proportion. Both hypo- and hyperthyroidism decreased the ratio of 20:4n-6/18:2n-6 in the majority of phospholipids. PTU decreased the unsaturation index in PC, PI and phosphatidylserine. It is concluded that thyroid state plays an essential role in the development of membrane phospholipid components in cardiac membranes during the early postnatal period.

Animals↗
PubMed2003

Salubrious effect of low molecular weight heparin on atherogenic diet-induced cardiac, hepatic and renal lipid peroxidation and collapse of antioxidant defences.

The present work showcases the distressing picture of oxidative stress in the cardiac, hepatic and renal tissues, in an experimental model based on early phase atherogenesis. The protection rendered by LMWH intervention forms part of the same study. Male Wistar rats of 140 +/- 10 g were categorized as four groups. One group served as untreated control and another as LMWH drug control group. Two groups were fed a hypercholesterolemic atherogenic diet (rat chow supplemented with 4% cholesterol, 1% cholic acid and 0.5% thiouracil; CCT diet) for 2 weeks; one of these groups received LMWH treatment of 300 microg/day/rat for 7 days. The biochemical index of tissue lipid peroxidation (LPO) was assessed in terms of MDA formation. Heart, liver and kidney tissues of CCT-diet fed rats showed significantly elevated levels of LPO. In the early phase atherosclerotic group, we observed abnormal changes in the activities/levels of tissue enzymic (superoxide dismutase, catalase and glutathione peroxidase) and non-enzymic (reduced glutathione, ascorbate and alpha-tocopherol) antioxidants. We report normalized LPO levels and antioxidant defences in the atherogenic rats treated with LMWH. Thus the present study highlights the hepatic, cardiac and renal oxidative changes induced by experimental atherogenesis, and the protection rendered by LMWH treatment in atherosclerotic cardiovascular conditions.

Animals↗
PubMed2000

A family of candidate taste receptors in human and mouse.

The gustatory system of mammals can sense four basic taste qualities, bitter, sweet, salty and sour, as well as umami, the taste of glutamate. Previous studies suggested that the detection of bitter and sweet tastants by taste receptor cells in the mouth is likely to involve G-protein-coupled receptors. Although two putative G-protein-coupled bitter/sweet taste receptors have been identified, the chemical diversity of bitter and sweet compounds leads one to expect that there is a larger number of different receptors. Here we report the identification of a family of candidate taste receptors (the TRBs) that are members of the G-protein-coupled receptor superfamily and that are specifically expressed by taste receptor cells. A cluster of genes encoding human TRBs is located adjacent to a Prp gene locus, which in mouse is tightly linked to the SOA genetic locus that is involved in detecting the bitter compound sucrose octaacetate. Another TRB gene is found on a human contig assigned to chromosome 5p15, the location of a genetic locus (PROP) that controls the detection of the bitter compound 6-n-propyl-2-thiouracil in humans.

Amino Acid Sequence↗
PubMed1998

Reduced sympathetic noradrenergic neurotransmission in the tail artery of Donryu rats fed with high cholesterol-supplemented diet.

1. Sympathetic neurotransmission and noradrenaline content of the tail artery of Donryu rats fed for 2 months with a cholesterol-supplemented diet enriched with 4% cholesterol, 1% cholic acid, 0.5% thiouracil (CCT), were examined. 2. Total serum cholesterol level of CCT fed rats (7.05 +/- 1.77 mg ml(-1), n = 8) was significantly greater than lab-chow fed controls (2.58 +/- 0.32 mg ml(-1), n = 8). Low density lipoprotein level was also significantly increased in CCT-fed (1.79 +/- 0.26 mg ml(-1), n = 8) compared with control fed rats (1.35 +/- 0.25 mg ml(-1), n = 8) but plasma levels of triglyceride and high density lipoproteins did not differ significantly between the two groups. 3. Contractile responses of the arterial rings to transmural nerve stimulation (65 V, 0.1 ms, 4-64 Hz, 1 s), were markedly attenuated in the CCT fed animals compared with the controls. This reduction involved the noradrenergic rather than purinergic component of sympathetic transmission. 4. Vasoconstrictor responses to exogenous noradrenaline (0.01-300 microM) and adenosine 5'-triphosphate (0.3-1000 microM) were unaffected by CCT diet, indicating prejunctional alteration of sympathetic neurotransmission during CCT-induced hyperlipidaemia. 5. The noradrenaline content of the tail arteries of CCT fed animals (2.64 +/- 0.36 ng mg(-1), n = 6) was significantly lower than that of controls (3.82 +/- 0.32 ng mg(-1), n = 6). 6. These findings show that chronic treatment of Donryu rats with a cholesterol-supplemented diet led to altered levels of circulating lipid fractions accompanied by attenuated sympathetic noradrenergic neurotransmission and reduced noradrenaline content of the rat tail artery.

Animals↗