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M P Hegarty

Publications and source records attributed to M P Hegarty.

At least 19 recordsLinked to original sources
PubMed1999

Analysis of the amino acid indospicine in biological samples by high performance liquid chromatography.

Indospicine is a hepatotoxic amino acid that accumulates in the meat of horses that consume the legume Indigofera linnaei. A method to determine indospicine concentration in biological samples using an amino acid analyser has been reported, but the analysis time is long and therefore not suited to the analysis of large numbers of samples. A rapid and reliable method was developed for the analysis of indospicine in horsemeat and serum using High Performance Liquid Chromatography. Horsemeat and serum were extracted with either water or 0.01 N hydrochloric acid, respectively, and deproteinized by ultrafiltration. Precolumn derivatization of samples with phenylisothiocyanate was followed by separation of indospicine from other amino acids on a Pico-Tag C 18 column and UV detection at 254 nm. The calibration curves for indospicine in horsemeat extract were linear over the concentration range 0.4 microg ml(-1) to 20 microg ml(-1), while for indospicine in serum, the linear range was from 0.17 microg ml(-1) to 16.67 microg ml(-1). The mean recovery of indospicine in horsemeat extract was 87.2 +/- 6.8% and in serum was 97.3 +/- 9.9%. Analysis time for indospicine in horsemeat samples was 31 min and in serum samples was 36 min.

Animals↗
PubMed1996

Effects of the naturally occurring arginine analogues indospicine and canavanine on nitric oxide mediated functions in aortic endothelium and peritoneal macrophages.

The ability of the naturally occurring non-protein toxic amino acids indospicine and canavanine to inhibit nitric oxide synthesis was tested in isolated rat aorta and cultured rat peritoneal macrophages. Both compounds inhibited acetylcholine induced relaxation of rat aorta contracted with noradrenaline, a process mediated by nitric oxide generated in vascular endothelium. Nitric oxide is generated in vascular endothelium from arginine by a constitutive nitric oxide synthase. Indospicine and canavanine also increased superoxide mediated reduction of cytochrome c by phorbol myristate acetate stimulated rat peritoneal macrophages. The increase in superoxide under these conditions was due to decreased nitric oxide synthesis. Macrophage synthesis of nitric oxide is mediated by an inducible form of nitric oxide synthase. It is concluded that indospicine and canavanine are inhibitors of constitutive and inducible nitric oxide synthases and it is suggested that the toxicity associated with these compounds could be related to this activity.

Animals↗
PubMed1988

Hepatotoxicity to dogs of horse meat contaminated with indospicine.

An outbreak of liver disease which killed more than 30 dogs at Alice Springs was associated with feeding meat from horses, some of which had developed Indigofera linnaei poisoning (Birdsville horse disease). Affected livers were small, nodular and yellow. There was associated jaundice, ascites, elevation of alanine aminotransferase levels in serum, a tendency to bleed, and signs of hepatic encephalopathy. Histologically, livers showed periacinar necrosis, collapse and haemorrhage, with severe swelling, vacuolation and cholestasis in remaining hepatocytes. Indospicine, a toxic amino acid found in the genus Indigofera, was detected in samples of suspect horsemeat. Experimental feeding of horsemeat containing 16 mg indospicine/kg for 32 days produced periacinar necrosis and hepatocellular swelling in 2 dogs, although neither died nor showed clinical illness. In another experiment, intakes of as little as 0.13 mg indospicine/kg bodyweight/day for 70 days produced periacinar liver lesions, and indospicine concentrations in serum, muscle and liver rose during this period to 3.9, 7.9 and 17.5 mg/kg, respectively. It was concluded that meat from horses grazing I. linnaei can be hepatotoxic for dogs, and that this toxicity may be related to its indospicine content.

Amino Acids↗
PubMed1987

3,4-Dihydroxypyridine: a potential antithyroid drug.

3,4-Dihydroxypyridine (3,4-DHP), a goitrogenic derivative of the plant amino acid mimosine, has no SH-group, in contrast to conventional antithyroid agents such as methimazole (MMI) and propylthiouracil (PTU). The current in vitro study shows that 3,4-DHP, like MMI and PTU, inhibits iodination of human thyroglobulin and interferes with mitogenic activation of human lymphocytes. This, together with a very low murine bone marrow toxicity, probably related to the absence of an SH-group, makes 3,4-DHP a potential antithyroid drug.

Antithyroid Agents↗
PubMed1984

Chronic active hepatitis in mice induced by 3-hydroxy-4-pyrone.

Chronic active hepatitis was selectively induced in mice by the feeding of a diet containing 3-hydroxy-4-pyrone (0.5% by weight) for periods of 6 weeks and longer. This model should be of particular value in elucidating the pathogenesis of drug-induced forms of chronic active hepatitis. Maltol (3-hydroxy-2-methyl-4-pyrone) did not produce any liver lesion.

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↗
PubMed1979

The goitrogen 3-hydroxy-4(1H)-pyridone, a ruminal metabolite from Leucaena leucocephala: effects in mice and rats.

Mice fed a diet containing 1% (w/w) 3-hydroxy-4(1H)-pyridone (DHP) developed goitre even with a diet high in iodine whereas mimosine (0.5% w/w) did not produce goitre even with a low-iodine diet. Thyroid enlargement was apparent (measured morphometrically) by the 7th week and was advanced by the 11th week. Histologically the goitre was hyperplastic in type. No marked histological changes were found in other organs of mice fed DHP or any organs of mice fed mimosine, except for some atrophy of hair follicles. A single intragastric dose of DHP inhibited the uptake of 125I by the thyroid in the rat but an equivalent dose of mimosine did not. Evidence is presented that the inhibition occurs at the iodine binding step, as with methyl thiouracil, rather than at the iodide trapping step, as with thiocyanate. Chronic treatment of mice with DHP, as with 6-methyl thiouracil, increased the avidity of the thyroid in taking up 125I. The major conjugated form of DHP in mammals, DHP-3-O-glucuronide, was almost as effective a goitrogen as the unconjugated compound when given by mouth but considerably less active than the free form in the blood stream. It was concluded that DHP is a potent antithyroid compound of the thiouracil type with low general toxicity, since mammals can tolerate a level of intake sufficient to produce goitre in spite of iodine supplementation.

Animals↗
PubMed1978

Comparative toxicities of mimosine and some chemically related compounds to mouse bone marrow cells in liquid culture.

Mimosine, a plant amino acid which is toxic in mammals, was shown to be a potent inhibitor of incorporation of [3H]thymidine in mouse bone marrow cells in liquid culture (is greater than 70% inhibition at a concentration of 2 x 10(-4) M). To determine the parts of the molecule responsible for the inhibitory mechanism the effects of 13 chemically related compounds were examined in this system. The structural features necessary for inhibitory activity of the 4(1H)-pyridones were (1) the 3-hydroxyl-4-oxo function of the pyridone ring together with (2) an alpha-alanine or a 2-aminoethyl side chain. Compounds based on several other hydroxy heterocyclic functions were either weakly active or inactive. 3-Hydroxy-4(1H)-pyridone, the goitrogen to which mimosine is converted in ruminants, was only slightly inhibitory. These results are compared with published information on the effects of some of these compounds on other types of mammalian cells in vitro. The mouse bone marrow system in which inhibition of incorporation of [3H]thymidine is used as an index of cytotoxicity was shown to be sensitive and reproducible, and could be useful for structure-activity investigations of other cytotoxic compounds.

Animals↗
PubMed1976

Prostaglandin in the saliva of the cattle tick Boophilus microplus.

Previous studies of saliva from engorged female cattle ticks revealed a component which induced contration of some isolated smooth muscles. Fractionation and further characterisation have shown that this substance is of the "slow-reacting" type, but that it is neither a bradykinin nor slow-reacting substance of anaphylaxis. The substance is deactivated by incubation with 15-hydroxprostaglandin dehydrogenase and its pharmacological properties also support its classification as a prostaglandin. A second pharmacologically-active component has now been found in the saliva but has not yet been characterised.

Animals↗
PubMed1975

Effects on the liver in the rat of ingestion of Indigofera spicata, a legume containing an inhibitor of arginine metabolism.

The non-protein amino acid indospicine, which occurs in the free state in high concentration in the tropical pasture legume Indigofera spicata, causes toxic liver lesions in ruminants. Indospicine is a specific antagonist of arginine and an inhibitor of protein synthesis. The liver lesion was studied in rats at four dose levels by feeding diets containing 96, 48, 24 and 15 per cent. of the seed. The too higher levels caused death of most animals in 2-6 wk. Females were more susceptible than males. The rats fed the 24 per cent. seed diet developed a nodular cirrhosis by 6 wk and survived up to 18 wk. The rats fed the 15 per cent. seed diet developed cirrhosis at 16 wk and survived up to 28 wk. Prior to the onset of cirrhosis the liver showed a characteristic lesion consisting of hepatomegaly, periportal fatty change, portal cellularity due to proliferation of ovoid and cuboidal duct cells, gross enlargement of the hepatocyte cytoplasm nuclei and nucleoli in spite of brisk mitotic activity, and focal centrilobular necrosis. The lesion was interpreted as a restricted hepatic response to a growth stimulus, possibly the mobilisation of tissue amino acids. Improvement occurred in the rats fed the two lower dosage levels after nodular cirrhosis developed, producing a new parenchyma. An attempt is made to relate the lesions to the biochemical derangement induced by a specific amino acid antagonist.

Amino Acids, Diamino↗
PubMed1975

Fate of mimosine administered orally to sheep and its effectiveness as a defleecing agent.

Mimosine was administered orally to Merino sheep once daily for periods of 1-3 days, either as the isolated compound or in the foliage of Leucaena leucocephala. A single daily dose of mimosine of 450 or 600 mg/kg body weight was effective for defleecing sheep. A daily dose rate of 300 mg/kg was effective for defleecing sheep if given on two successive days. The effectiveness of a treatment for defleecing sheep was related to the concentration of mimosine in plasma following dosing; defleecing ensued when the concentration of mimosine in plasma was maintained above 0-1 mmol/l for at least 30 h. The main products excreted in urine were mimosine and 3,4-dihydroxypyridine (DHP); small amounts of mimosinamine were also excreted. During the first day following dosing, the major excretory product was mimosine; DHP was an important component during the second and third days. In the three days following the start of dosing, between 32 and 53% of the mimosine given was accounted for as mimosine in the urine. Following an intravenous infusion of mimosine, no DHP was detected in urine; most of the mimosine was excreted intact but a small amount (c. 9%) was excreted as mimosinamine.

Administration, Oral↗