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PubMed1983

Structure-activity relationship of ligands of the pyrimidine nucleoside phosphorylases.

Eighty-seven pyrimidine base and nucleoside analogs were evaluated as inhibitors of uridine phosphorylase (UrdPase) and thymidine phosphorylase (dThdPase). These findings, together with an extensive literature review, have allowed construction of structure-activity relationships for the binding of ligands to UrdPase and dThdPase and provide a basis for the rational design of new inhibitors of these enzymes. Additionally, 2,6-pyridinediol and 6-benzyl-2-thiouracil have been identified as being potent inhibitors of UrdPase and dThdPase respectively.

Animals↗
PubMed1983

Human kidney thiopurine methyltransferase. Purification and biochemical properties.

Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurines and thiopyrimidines. Human kidney TPMT was purified over 300-fold and its biochemical properties were determined. TPMT was "soluble" and had a molecular weight of approximately 36,000 daltons as estimated by gel filtration chromatography. The pH optimum of the purified TPMT was 6.7. "True" Km values for 6-mercaptopurine (6-MP) and S-adenosyl-L-methionine (SAM), the two cosubstrates for the reaction, were 0.30 mM and 2.7 microM respectively. "Apparent" Km values for 6-thioguanine and 2-thiouracil, two other methyl acceptor substrates, were 0.55 and 2.0 mM respectively. Aliphatic thiol compounds were either poor substrates for TPMT or were not methylated. S-Adenosyl-L-homocysteine was a competitive inhibitor of TPMT when the varied substrate was SAM, and 6-methylmercaptopurine was a noncompetitive inhibitor with respect to 6-MP. Purified TPMT was neither activated nor inhibited by 1 mM Ca2+ or Mg2+, but exposure to reagents such as N-ethylmaleimide and ethacrynic acid that interact with sulfhydryl groups inactivated the enzyme. Tropolone inhibited TPMT with a Ki of approximately 0.85 mM. Finally, human kidney TPMT activity could be distinguished from human kidney thiol methyltransferase (EC 2.1.1.9) activity on the basis of subcellular distribution, substrate specificity, kinetic characteristics and differential sensitivity to inhibitors.

Cations, Divalent↗
PubMed1984

Effects of propylthiouracil on D-galactosamine hepatotoxicity in the rat. Evidence for a non-thyroidal effect.

The cytoprotective effects of propylthiouracil (PTU) were studied in rats treated with the hepatotoxin D-galactosamine (D-GNH2). Five days of PTU pretreatment prior to D-GNH2 caused hypothyroidism and a significant reduction in liver injury as assessed by serum transaminase levels. When PTU was administered as a single dose with D-GNH2, significant decreases in transaminase also occurred at times when thyroid function was unchanged. Furthermore, aminopyrine oxidation showed significant impairment after D-GNH2 and was normalized by one dose of PTU. Further studies were carried out in thyroidectomized rats. PTU caused significant reductions in transaminase levels when given for 5 days pretreatment or as a single dose. Animals receiving pretreatment with PTU plus thyroxine (T4) also had significant decreases in serum transaminase. The antithyroid drug methimazole also had a hepatoprotective effect, while two other potent antithyroid compounds (2-thiouracil and 2-thiobarbituric acid) did not. These data suggest that PTU can protect against liver injury induced by D-GNH2, that the effect is independent of thyroid function, and that this effect is not common to all thiol-containing antithyroid drugs.

Aminopyridines↗
PubMed1985

Effect of thyroid state on histamine H1 receptors in adult and developing rat brain.

The effect of thyroid status on histamine H1 receptors in adult and developing rat brain was investigated using the (3H) mepyramine binding assay. Hypothyroidism induced by treatment with 6-n-propyl-2-thiouracil resulted in a 31% decrease in the density and total content of adult rat brain (3H) mepyramine binding sites and a significant retardation of the developmental increase in H1 receptor binding in neonates. At 30 days of age, when euthyroid rats reached binding levels of the adult, hypothyroid animals presented reductions of 22 and 39% in (3H) mepyramine bound per unit weight and per brain respectively. In contrast, hyperthyroidism induced by treatment with L-thyroxine did not alter H1 receptor numbers in the adult rat brain but accelerated the developmental increase in (3H) mepyramine bound per unit weight that reached normal adult levels by 21 days of age. The results suggest that thyroid dysfunction during early life and adulthood may cause derangements of the histaminergic system in the brain.

Age Factors↗
PubMed1985

Inhibitory effect of propylthiouracil on the development of metabolic tolerance to ethanol.

Chronic ethanol administration (4-5 weeks) to female spontaneously hypertensive (SH) rats led to a marked increase in the rate of ethanol metabolism. This was accompanied by an increase in hepatic alcohol dehydrogenase (ADH) and by an increase in the rate of oxygen consumption in perfused livers of these animals. Treatment with the antithyroid drug 6-n-propyl-2-thiouracil (PTU) during the last 9 days (40 mg/kg/day) of the chronic administration of ethanol reduced hepatic oxygen consumption, resulting in a net diminution of the metabolic tolerance to ethanol, despite a further elevation in ADH activity. In these animals, microsomal ethanol-oxidizing system (MEOS) activity was not affected by chronic ethanol administration or by treatment with PTU. Data strongly suggest that in the female SH rat all the metabolic tolerance to ethanol proceeds via the ADH pathway, and that the increase in hepatic oxygen consumption is more important in the development of metabolic tolerance to ethanol than the increased ADH levels.

Alcohol Dehydrogenase↗
PubMed1986

Inhibition of hepatic glutathione transferases by propylthiouracil and its metabolites.

The effects of propylthiouracil (PTU) and its metabolites on the activity of GSH transferases were examined using rat liver cytosol. PTU inhibited the enzyme activity toward both CDNB and DCNB in a concentration-dependent manner. At the concentration of 10 mM, PTU caused 25% inhibition, which was the maximum effect. PTU derivatives such as propyluracil and thiouracil showed the same effect as the parent compound. On the other hand, S-oxides of PTU such as PTU-SO2 and PTU-SO3, which were chemically synthesized by the oxidation of PTU, were more potent inhibitors of GSH transferases than the parent PTU. A significant inhibition was observed at a concentration of 0.1 mM of PTU S-oxides. At a concentration of 10 mM the S-oxides caused an 80% inhibition of the enzyme activity. PTU inhibited the transferase activity by competing with GSH but the S-oxides of PTU acted by another mechanism. In contrast to the effect on GSH transferases, PTU-SO3 had a weak inhibitory effect on GSH peroxidase activity. Thus, oxidation of PTU leads to products which are potent inhibitors of GSH transferases.

Animals↗
PubMed1987

Assessment of the biopotency of anti-thyroid drugs using porcine thyroid cells.

The effect of six drugs on the uptake and organification of iodide by porcine thyroid cells stimulated with bovine TSH (10 miU/L) has been investigated. The drugs fall into two categories: the peroxidase inhibitors, methimazole (MMI), 2-thiouracil (2-TU) and 3-amino 1,2,4 triazole (3-ATA) and the ionic inhibitors, lithium chloride (LiCl), potassium perchlorate (KC10(4], and sodium iodide (NaI). All the drugs led to a dose-related inhibition of iodide metabolism. The most potent effect on iodide uptake was seen with NaI which inhibited this function by 20% even at 10(-8) mol/l. In contrast, the most potent effect on iodide organification was observed with methimazole which led to a 25% inhibition at 10(-8) mol/l. The concentrations of drug which gave rise to a 50% inhibition of iodide uptake were (mumol/l) 0.26 (NaI), 3.5 (KClO4), 9.7 (2-TU), 15 (MMI), 26 (3-ATA), and 1500 (LiCl). The comparable figures for organification were 0.13 (MMI), 0.18 (2-TU), 0.23 (NaI), 1.2 (3-ATA), 15 (KClO4) and 1300 (LiCl). We conclude that this in vitro system has considerable potential for the assessment of potency and possible bioassay of anti-thyroid drugs of varying structures and sites of action.

Animals↗
PubMed1989

Inhibition of uridine phosphorylase from Giardia lamblia by pyrimidine analogs.

Fifty-six pyrimidine analogs were tested as possible inhibitors of uridine phosphorylase from Giardia lamblia. Values of Ki were determined for eight of these which demonstrated an inhibition greater than 60% under the standard conditions of uridine at 1 mM (approximately 1.5 times the Km) and inhibitor at 1 mM. All were competitive with respect to uridine. The most effective inhibitors were uracil analogs substituted at the C-5 position with electron withdrawing groups (nitro groups or halogens). The inhibitory effect at the 5-position appeared to be further enhanced by substitution at the C-6 position with electron releasing groups. The order of effectiveness as inhibitors was 6-methyl-5-nitrouracil greater than 6-amino-5-nitrouracil greater than 5-benzylacyclouridine greater than 5-nitrouracil greater than 5-fluorouracil greater than 5-bromouracil greater than 6-benzyl-2-thiouracil greater than 1,3-dimethyluracil with Ki values of 10, 12, 44, 56, 119, 230, 190 and greater than 1000 microM, respectively. The compounds were also effective inhibitors of the thymidine phosphorylase activity of the enzyme. The effect of the more potent compounds on G. lamblia in in vitro culture are currently under investigation.

Animals↗
PubMed1979

Antithyroid and antiperoxidase activity of tropolone and 3-hydroxy-4-pyrone.

Tropolone (TR) and 3-hydroxy-4-pyrone were investigated for antithyroid activity following the finding that the 2-hydroxy-oxo pyridine, 3-hydroxy-4(1H)-pyridone (DHP, I), is goitrogenic. Both compounds inhibited the thyroidal uptake of radioiodine in rats and resembled the thioamide drugs in inhibiting the organic binding of iodine by the thyroid gland rather than the trapping of iodide, but were weaker binding inhibitors than 6-methyl-2-thiouracil (MeTU). Both compounds also inhibited the iodination of bovine serum albumin and thyroglobulin, catalyzed by thyroidperoxidase (TPO), lactoperoxidase (LPO), chloroperoxidase (CPO) and horseradish peroxidase (HPO) in vitro. The inhibitory effect of TR but not that of 3-hydroxy-4-pyrone was antagonized by ferrous ions. When fed to mice at levels of intake expected to produce goitre both compounds were toxic and caused severe liver damage. Thyroid enlargement was not observed in any of these feeiding experiments, but the thyroids of mice fed 0.1% TR showed moderate hyperplasia. It was concluded that both compounds are weakly goitrogenic. Hyperactivity was observed in the mice fed TR which may be associated with inhibition of catechol methyl transferase (COMT).

Animals↗
PubMed1980

Decreased number of beta-adrenoceptors in cerebral cortex of hypothyroid rats.

The influence of thyroid hormone deficiency on beta-adrenoceptors in the rat cerebral cortex was investigated using the 3H-dihydroalprenolol binding assay. The maximal number of binding sites (Bmax) and the dissociation constants (KD) were determined in the brain tissue from euthyroid animals and from rats made hypothyroid by feeding 6-propyl-2-thiouracil. Hypothyroidism resulted in a 37% decrease in beta-adrenoceptor density (Bmax). The dissociation constants (KD) of both groups were not significantly different.

Animals↗
PubMed1989

Quantitation of oil red O staining of the aorta in hypercholesterolemic rats.

A technique is described which provides morphologic and quantitative data on the amount of oil red O (ORO) staining in thoracic aortas of rats fed a high cholesterol diet. Samples are stained with ORO, the dye is extracted, and the concentration of ORO in the extract is measured colorimetrically. Wistar rats fed ad libitum either standard chow (control group: n = 15) or chow supplemented with 4% cholesterol, 1% cholic acid, and 0.5% thiouracil (CCT group: n = 23) were maintained on these diets for 1, 3, 6, 9, or 12 months. Plasma cholesterol levels averaged overall 87 and 737 mg/dl for the control and CCT groups, respectively. Animals were killed under anesthesia by perfusion fixation with formalin or glutaraldehyde, and samples of thoracic aorta were stained with ORO. After microscopic study en face and measurement of surface area, the ORO was extracted in chloroform-methanol (2:1). Concentrations of ORO (microM) were determined from a standard curve and expressed as microM/mm2 of aorta. Aortas of CCT animals showed progressive diet- and time-dependent increases in the amount of ORO staining compared to controls. We conclude that this method yields reliable quantitative data applicable to studying atherosclerosis in small animals.

Animals↗
PubMed1993

Different thyroid hormone-deiodinating enzymes in tilapia (Oreochromis niloticus) liver and kidney.

Enzymes catalyzing the outer ring deiodination (ORD) of iodothyronines are important for the regulation of thyroid hormone bioactivity. We have studied ORD of thyroxine (T4) and 3,3',5'-triiodothyronine (rT3) in liver and kidney microsomes of fish, i.e. tilapia (Oreochromis niloticus). Tilapia kidney contains an enzyme which resembles the mammalian selenoenzyme type I iodothyronine deiodinase (ID-I) with respect to substrate preference (rT3 > T4) and high (approximately microM) Km values, but is much less sensitive to selenocysteine (Sec)-targeted inhibitors, including 6-propyl-2-thiouracil (PTU). In contrast, tilapia liver contains an enzyme very similar to mammalian type II deiodinase (ID-II) with respect to substrate preference (T4 > rT3), low (approximately nM) Km values, and lack of sensitivity to Sec inhibitors.

Animals↗
PubMed1986

Comparison of type I 5'-deiodination of thyroxine and of reverse-triiodothyronine in rat and chicken liver homogenates.

The characteristics of 5'-deiodination in the chicken liver have been compared to those in the rat. Using 6-n-propyl-2-thiouracil (PTU) at 1 mM in vitro, it was shown that, in accordance with former in vivo studies, only type I 5'-deiodinase exists in the liver of the chicken. When PTU was used in a concentration (10 microM) close to its Ki species differences could be demonstrated as for PTU sensitivity. 5'-Deiodinase in the chicken liver was more susceptible against the inhibitor. The early thiol-independent phase of deiodination was longer in the chicken than in the rat. Reverse-triiodothyronine (r-T3) seemed to be a more suitable substrate for this enzyme in the chicken when compared to either T4 degradation or r-T3 degradation in the rat. It is concluded that major characteristics of 5'-deiodination in the chicken are similar to those in the rat; however, the slight variances observed might explain some species differences found earlier.

Animals↗
PubMedDate not supplied

Effects of dextrothyroxine on hyperlipidemia and experimental atherosclerosis in beagle dogs.

Beagle dogs, 24 +/- 6 months old, fed a thiouracil-free semi-synthetic diet containing hydrogenated coconut oil and cholesterol (SS diet) for 12 months, developed marked hyperlipidemia and severe atherosclerosis. SS diet produced a marked elevation of serum cholesterol, triglyceride, phospholipid, and beta-lipoprotein and severe atherosclerosis in large and small arteries. Intimal fatty lesions were always present in the abdominal aorta and many of its branches. Large and small coronary arteries showed similar lesions. The degree of atherosclerosis was directly related to circulating lipid levels. Dextrothyroxine, at dose levels of 0.1 (equivalent to normal human dose) and 0.5 mg/kg body weight, produced a significant dose related lowering of serum lipids and was associated with a markedly decreased severity of aortic and coronary artery lesions. Untreated control dogs that were maintained on purina dog meal developed neither hyperlipidemia nor atherosclerosis.

Animals↗
PubMed1978

Experimental hyper-beta-lipoproteinemia and its amelioration by a novel hypolipidemic agent.

Experimental models for hyper-beta-lipoproteinemia were established in rats and the effects of certain hypolipidemic drugs were studied with these models. In the hyperlipemia induced in rats by feeding a high cholesterol diet, Y-9738 [ethyl 2(4-chlorophenyl)-5-ethoxy-4-oxazoleacetate] produced a dose-dependent reduction of serum cholesterol: such hypolipidemic activity was estimated to be about 7 times as great as that of clofibrate. On the other hand, clofibrate induced hepatomegaly at 100 mg/kg, whereas Y-9738 did not at this dosage, which is about 10 times the effective dose. Hyperlipemia induced by high cholesterol and thiouracil was characterized by increased beta-lipoprotein (heparin-calcium and disc electrophoresis). In this model, Y-9738 showed a dose-dependent lowering effect on beta-lipoprotein cholesterol with a marked decrease in the beta/alpha lipoprotein ratio. A tendency was noted for alpha-lipoprotein to be increased. In contrast, clofibrate exerted no effect on this hyper-beta-lipoproteinemia. These results suggest that the above models may be of value in exploring hyper-beta-lipoproteinemia and that Y-9738 may be more useful than clofibrate in the therapy of hyperlipemia.

Animals↗
PubMed1994

Effect of cholesterol-supplemented diet in heritable hyperlipidemic Yoshida rats: functional and morphological characterization of thoracic aorta.

In this study we have considered the possibility of inducing vascular damage in Yoshida Pittsburg (YOS) rat, an inbred strain which has endogenous hyperlipidemia without vascular atherosclerotic damage. Cholesterol-enriched diet (4% cholesterol plus 1% cholic acid and 0.5% thiouracil) was administered to YOS rats, in order to induce atherogenesis. The results indicate that, despite significant increase in serum (about 2-fold) and aortic tissue cholesterol (about 6-fold), no morphological damage occurred. A reduction in acetylcholine-mediated relaxation (of about 37%) was observed. No inhibition of ATP- or sodium nitrite-induced relaxation, or of contraction induced by norepinephrine was seen. Serum triglyceride concentration did not vary after administration of a cholesterol-enriched diet. Our results suggest that in heritable hyperlipidemic Yoshida rat, after 2 months of cholesterol-enriched diet, despite increased serum cholesterol levels, no atheromatous plaque developed on the aortic wall. Impaired vascular function and reductions in the response to acetylcholine were related to changed endothelial cell function. Administration of a high cholesterol diet to YOS rat may represent a new model of mixed endogenous and exogenous hyperlipidemia that can resemble many human dislipidemic diseases and therefore may become a useful tool for the study of isolated endothelial dysfunction.

Acetylcholine↗
PubMed1986

Substrate specificity of iodothyronine 5'-deiodinase in rat liver homogenates and its requirements of divalent cations in vitro.

Studies were carried out to compare the 5'-deiodination reactions of thyroxine (T4) and 3,3'-5'-triiodothyronine (rT3) in 2.5% rat liver homogenates. The 5'-deiodinase activity was assayed by the 3,5,3'-triiodothyronine (T3) produced from T4 or by 125I-rT3. Under our experimental conditions, the two 5'-monodeiodination reactions resulted in similar apparent KMs: 1.5 microM for T4 and 1.1 microM for rT3. However, the apparent Vmax values of T4 and rT3 deiodination reactions were, respectively, 0.91 and 222 pmol/mg protein/min. Both reactions were stimulated by thiol reagents but only rT3 deiodination showed complete thiol dependence. The inhibitory effect of 6-propyl-2-thiouracil on the 5'-deiodination of rT3 was at least 50 fold greater than that of T4. The divalent ion requirement of the deiodination system was tested with CaCl2, MgCl2, and ZnCl2 at a range of concentrations. Zinc ion appeared to be a potent inhibitor in both T4 and rT3 deiodination systems. Only the 5'-deiodination of rT3 was inhibited slightly by low concentrations of calcium and magnesium ions. Our results suggest that based on their apparently distinct regulation mechanisms, the 5'-monodiodination of T4 and rT3 in rat liver homogenates is likely mediated by more than one enzyme, despite the similarity of observed KMs.

Animals↗
PubMed1977

Clearance of chylomicron triacylglycerol and cholesteryl ester from the plasma of streptozotocin-induced diabetic and hypercholesterolemic hypothyroid rats.

Labeled chylomicrons in thoracic duct lymph were collected after test meals containing 14C cholesterol and 2-3H glyceryl trioleate and were given by intravenous injection to groups of control rats, rats made diabetic by treatment with streptozotocin, and rats made hypothyroid and hypercholesterolemic by a diet containing cholesterol, peanut oil, cholic acid, and thiouracil. In the diabetic rats clearances from the plasma of chylomicron triacylglycerol and cholesteryl ester were impaired. A large variability in triacylglycerol clearance in diabetic rats was ascribed to variability in plasma triacylglycerol concentrations. Adipose tissue lipoprotein lipase activity was not impaired in the female diabetic rats used in this study. In the hypothyroid hypercholesterolemic rats chylomicron cholesteryl ester clearance from the plasma was impaired but chylomicron triacylglycerol was cleared efficiently, and adipose tissue lipoprotein lipase activity was similar to or greater than activity in controls. Ten minutes after intravenous injection most plasma radioactivity was recovered in lipoproteins of density less than 1.006 g/ml in all groups of rats, but relatively more was recovered at this density in both treatment groups. We suggest that chylomicron remnants accumulate in the plasma and contribute to the development of hyperlipemia in both treatment groups, but that the remnants formed in the diabetic rat are less depleted of triacylglycerol than the remnants formed in the hypothyroid hypercholesterolemic rat. It is suggested that factors other than measured lipoprotein lipase activities of adipose tissues may be important in determining the initial extent of hydrolysis of chylomicron triacyglycerol. We propose that the hypercholesterolemic hypothyroid rat is a useful model for the experimental production of the remnants of triacylglycerol-rich primary lipoproteins.

Animals↗