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Biomedical subjects

R J Huxtable

Publications and source records attributed to R J Huxtable.

At least 73 records · Page 4Linked to original sources
PubMed1992

Phospholipid methylation and taurine content of synaptosomes from cerebral cortex of developing rat.

Changes in taurine concentration and rate of methylation of phosphatidylethanolamine have been examined in rat brain synaptosomes over the course of development. At 7, 14, 21, 28 and 56 days of age, rats were injected i.p. with 300 microCi/kg [3H-methyl]methionine. Synaptosomes (P2B fraction) were isolated from the cerebral cortex 9 h later and incorporation of the methionine methyl group into phospholipid and protein was investigated. Synaptosomal taurine and methionine concentrations were determined at the same ages, as were the concentrations of the major classes of phospholipids (phosphatidylethanolamine, phosphatidylinositol, phosphatidylcholine and phosphatidylserine). Methionine concentration increased between day 7 and 14 and fell thereafter. Phospholipid methylation rates calculated from the specific activity of synaptosomal methionine were high from days 7 and 14 and then fell, whereas protein methionylation increased between day 7 and 28 and then decreased. A strong correlation was found between the taurine concentration of the synaptosome and phospholipid methylation rates during brain development. Protein methionylation rates, however, showed no correlation with taurine concentration.

Aging↗
PubMed1992

The pharmacology of extinction.

It is impossible to predict what compounds of pharmacological interest may be present in an unexamined species. The extinction of such species may result, therefore, in the loss of therapeutically significant compounds. The fact that science will never know what has been lost does not lessen the significance of the loss. A number of species are discussed to exemplify the potential loss. Ginkgo biloba is an ancient plant, apparently saved from a natural extinction by human intervention. From this tree, the ginkgolides have been isolated. These are potent inhibitors of platelet activating factor and hold promise in the treatment of cerebral ischemia and brain edema. Two species, the tree Taxus brevifolia and the leech Hirudo medicinalis, are threatened as a result of human activity. Both have recently yielded complex compounds of therapeutic importance. The antitumor agent, taxol, is obtained from T. brevifolia and the thrombin inhibitor, hirudin, is found in H. medicinalis. Catharanthus roseus, source of the anticancer agents vincristine and vinblastine, although not threatened, derives from a largely unexamined but severely stressed ecosystem of some 5000 plant species. In other examples, ethnobotanical knowledge of certain plants may be lost while the species survive, as exemplified by the suppression of the Aztec ethnobotany of Mesoamerica by the invading Spanish. Finally, the fallacy of the 'snail darter syndrome', where species may be viewed as too insignificant to worry about, is exposed by consideration of the pharmacological activities of a sea hare (a shell-less marine mollusc) and various leeches.

Ecology↗
PubMed1991

Identity of a biliary metabolite formed from monocrotaline in isolated, perfused rat liver.

A pneumotoxic pyrrolic metabolite, previously isolated from the bile when rat liver was perfused with the pyrrolizidine alkaloid, monocrotaline, has been identified as 7-glutathionyl-dehydroretronecine. The metabolite showed a TLC spot and HPLC peak corresponding with the latter compound, and a procedure for replacing the thioether group with an ethoxy group converted the metabolite to dehydroretronecine 7-ethyl ether, confirming that the glutathionyl moiety was attached to the 7-position of dehydroretronecine. The same metabolite was detected in bile from rat liver perfused with retrorsine, which is a diester alkaloid similar to monocrotaline, whereas it was not formed from heliotrine, an alkaloid lacking the 7-ester function.

Animals↗
PubMed1990

Activation and pulmonary toxicity of pyrrolizidine alkaloids.

Pyrrolizidine alkaloids unsaturated in the 1,2 position are hepatotoxins. Certain of them, such as monocrotaline, are also pneumotoxins, producing pulmonary arterial hypertension and right ventricular hypertrophy as a delayed response two weeks after administration. Pneumotoxicity is the result of hepatic metabolism, the lung itself being unable to bioactivate pyrrolizidine alkaloids. The changes produced in the lung following exposure to pneumotoxic pyrrolizidine alkaloids are reviewed, together with the factors and interventions which modify or influence these changes. In the main, the earliest changes are seen in vascular smooth muscle and in the interactions between the smooth muscle and the endothelium. The search to identify the pneumotoxic metabolite is reviewed. It is generally accepted that pyrroles, or dehydroalkaloids, are responsible for the toxicity of pyrrolizidines. However, the primary pyrroles are intensely reactive, hydrolyzing and polymerizing within seconds in aqueous solution. Evidence for and against the pneumotoxin being a primary pyrrole or a stabilized secondary conversion product of a primary pyrrole is discussed.

Animals↗
PubMed1990

The harmful potential of herbal and other plant products.

Herbs, herbal products, food additives and other dietary supplements derived from plants are widely consumed in many countries. The literature on intoxications from such behaviour is increasing. This article reviews some of the factors predisposing to intoxication from the use of herbs, with examples drawn largely from pyrrolizidine alkaloid-containing plants. Poisonings occur because of the misidentification of a plant, or the unknown or ignored toxicity of a correctly identified plant. Factors contributing to problems include the difficulties of identifying chopped, processed herbs or plant mixtures, persistent use of a toxic plant, variability in the toxic constituents of a plant, problems of nomenclature, adulteration and the difficulty in establishing the chronic toxic potential of a plant. Certain users of herbs are at high risk of intoxication. These include chronic users, those consuming large amounts or a great variety, the very young, fetuses, the elderly, the sick, the malnourished or undernourished and those on long term medication. Members of certain cultural groups in North America are also at higher risk. Certain plant toxins may be gender-selective in their action. To encourage discussion, some approaches to regulation are suggested, and some commonsense guidelines are given.

Humans↗
PubMed1990

Na+/K(+)-adenosine triphosphatase activity of pulmonary arteries after intoxication with the pyrrolizidine alkaloid, monocrotaline.

Na+/K(+)-Adenosine triphosphatase-dependent activities of K(+)- return relaxation and 86Rb uptake were studied in pulmonary arteries taken from rats with pulmonary hypertension induced by monocrotaline. Rats were given monocrotaline in drinking water, 20 mg/l, for 4 or more days. Isolated arteries were placed in tissue baths and contracted with norepinephrine or 5-hydroxy-tryptamine under K(+)-free conditions. The arteries relaxed when K+ was "returned" to the bath. Compared to arteries from untreated rats, arteries taken from rats pretreated with monocrotaline developed less force in response to contracting agents and did not relax to the same extent. After 4 days treatment with monocrotaline, the rate of relaxation of the arteries in response to K(+)-return was slower than that of arteries taken from untreated rats. Endothelial trauma or in vitro treatment with ouabain produced a similar decrease in the rate of relaxation. Uptake of radiolabeled Rb by perfused arteries was not altered by 4 days of monocrotaline pretreatment. Isolated lungs taken from monocrotaline-pretreated rats (5 days of ingestion of 20 mg/l of monocrotaline drinking water) accumulated similar quantities of 86Rb+ during 40-sec perfusions. Shorter perfusion times, 10 and 20 sec, resulted in greater rates of uptake of 86Rb- by lungs taken from monocrotaline-treated rats. Monocrotaline produced changes in both the mechanical and biochemical properties of pulmonary arteries after only 4 to 5 days. These changes were associated with ouabain-sensitive processes. It appears, therefore, that one of the early targets in monocrotaline intoxication is the Na+/K+ pump of the pulmonary arteries.

Animals↗
PubMed1989

Dose-response relationship in intoxication by the pyrrolizidine alkaloid monocrotaline.

Rats develop pulmonary hypertension over a 2-wk period of continuous ingestion of monocrotaline dissolved in drinking water (20 mg/l). The relationship between monocrotaline concentration and duration of exposure was investigated by giving male rats (initial body weight 100 g) monocrotaline in drinking water (5, 10, 20, 40, or 60 mg/l) for 0, 1, 2, 4, 6, 10, or 20 d. Rats were killed 20 d after initiating treatment, and increased lung and right ventricular to body weight ratios were measured as indices of pulmonary hypertension. The accumulative dose of monocrotaline delivered over a 10-d period using a drinking water concentration of 10 mg/l (18 mg/kg) produced the same degree of right ventricular hypertrophy and lung weight increases as the doses ingested over a 4-d period by rats consuming 20 or 40 mg/l monocrotaline water (14 and 29 mg/kg). Phenobarbital pretreatment did not substantially alter the time course of toxicity induced with 20 mg/l monocrotaline water. Ingestion of 60 mg/l monocrotaline water for 1 d (11 mg/kg) resulted in right ventricular hypertrophy at 20 d. Since accumulative doses of less than 11 mg/kg did not produce toxicity and all doses greater than 14 mg/kg did, this range may be considered a threshold for inducing toxicity. However, organ weight increases following threshold exposures reversed over a 4-wk period. Increases in the wall thickness of pulmonary arteries correlated with the development of right ventricular hypertrophy. Pulmonary inflammation was not an early response to monocrotaline administration, since there was no change in the proportion of cell types recovered in lung lavage fluid during the first 6 d of monocrotaline treatment.

Administration, Oral↗
PubMed1989

Effect of suckling and diurnal influences on the concentrations of taurine and other free amino acids in milk.

Factors affecting the taurine and free amino acid content of human milk from a single donor have been examined. Taurine concentration was highest during the transition from colostrum to milk, attaining 400 microM. Concentrations fell thereafter, reaching 150 microM at 115 d post partum. Other free amino acids showed an opposite developmental pattern. Samples collected immediately after infant feeding were systematically lower in taurine than those collected immediately before feeding, but the differences were relatively small. Concentrations of other amino acids were unaffected by suckling on day 4. On day 6, however, decreases ranged from 16 per cent for glutamate to 46 per cent for threonine. Samples collected every 2 h over a 72-h period on days 113 to 115 post partum showed no diurnal variation in taurine content, neither did samples collected over a 24-h period on days 4, 6, 11, and 12. Serine and glycine showed a similar lack of periodicity. Aspartate, alanine, glutamine, threonine and glutamate levels, on the other hand, were lowest in the early morning, and highest in the early afternoon. High to low ratios ranged from 1.7 for glutamate to 4.1 for aspartate. Sample collection for taurine, serine and glycine analysis can probably be made without concern as to time of day or relationship to infant feeding. For the other amino acids, however, these factors need to be considered.

Adult↗
PubMed1988

Taurine and osmoregulation. II. Administration of taurine analogues affords cerebral osmoprotection during chronic hypernatremic dehydration.

We have previously shown that in the cat, taurine is an osmoprotective molecule that lessens mortality, neurological morbidity, and brain-cell dehydration during chronic hypernatremic dehydration. We examined the ability of two taurine analogues to afford cerebral osmoprotection in rats. Pretreatment with guanidinoethane sulfonate, a competitive antagonist for beta-amino acid transport, as a 1% drinking solution for ten days led to a significant reduction in brain-cell dehydration. Thus, total brain-cell water was higher in experimental vs control animals (544.3 +/- 36.8 vs 478.2 +/- 12.7 mL/100 g of fat-free dry solids [FFDS]) and the difference was almost exclusively derived from the intracellular water compartment (452.7 +/- 27.3 vs 371.4 +/- 7.7 mL/100 g of FFDS). Pretreatment with taltrimide, a lipophilic taurine derivative (intraperitoneal injection of 200 mg/kg for four days), led to similar results. Total brain-tissue water was significantly higher in experimental vs control rats (507.6 +/- 18.8 vs 363.2 +/- 9.5 mL/100 g of FFDS), with the difference primarily derived from the intracellular water space (372.8 +/- 18.1 vs 221.3 +/- 13.1 mL/100 g of FFDS). These results suggest that the cerebral response to chronic hypertonic stress includes accelerated transmembrane flux of osmoprotective solutes in addition to mobilization from sequestered intracellular storage sites in an attempt to increase the cytosolic pool of osmotically active molecules.

Animals↗