The role of biotransformation in chemical-induced liver injury.
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The role of drug metabolism in chemical-induced liver injury is reviewed. Parameters for studying the formation of chemically reactive metabolites are discussed and the factors that alter the formation and covalent binding of reactive metabolites are selectively emphasized. Some of the experimental work that led to these concepts is discussed, especially the chemical toxicology of the hepatic injury produced by acetaminophen, bromobenzene, furosemide, isoniazid and iproniazid. (+info)
Role of extraneuronal mechanisms in the termination of contractile responses to amines in vascular tissue.
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1 The role of the uptake and release of agonist from extraneuronal sites in the termination of responses of rabbit aortic strips to amines was studied. 2 Strips were contracted with adrenaline or noradrenaline and after response plateau was reached, the muscle chambers were washed free of agonist and the relaxation in Krebs solution recorded. After inhibition of catechol-O-methyl-transferase, monoamine oxidase and neuronal uptake the relaxation rate was greatly prolonged. Evidence is provided that this very slow relaxation resulted from the accumulation of intact amine at extraneuronal sites during exposure to the agonist and its subsequent release past receptors due to a reversal of the concentration gradient after washout. 3 Pretreatment with the haloalkylamine, GD-131 (N-cyclohexylmethyl-N-ethyl-beta-chloroethylamine), an inhibitor of extraneuronal uptake, returned the slow relaxation rate after enzyme inhibition towards that of control strips. By blocking the extraneuronal transport of amines their accumulation at intracellular loci after enzyme inhibition was prevented. 4 The effects of GD-131 and 17beta-oestradiol on the relaxation rate of untreated strips contracted by adrenaline and noradrenaline confirmed that extraneuronal uptake to sites of enzymatic activity is the major mechanism terminating their action. 5 Inactivation of extraneuronal transport sites by GD-131 was prevented by protecting them with 17beta-oestradiol or normetanephrine during exposure to the haloalkylamine, pointing to a common site of action of these agents on a specific carrier system for amines. 6 Evidence is presented that the relaxation from contractions induced by histamine and 5-hydroxytryptamine also involves extraneuronal accumulation and release, probably by an uptake process which is identical to the one for catecholamines. (+info)
Serotonin transport by cultured bovine aortic endothelium.
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Endothelial cells isolated from bovine aortas without prior treatment with enzymes were cultured in RPMI 1640 medium containing 17% fetal calf serum and antibiotics. The endothelial cells at confluency (7 days) were similar to endothelium in situ or to freshly isolated endothelial cells from blood vessels as seen by light, scanning, and electron microscopy. Cultured and freshly isolated indothelial cells exposed to labeled serotonin, even in the presence of iproniazid (5 x 10-4M), took up approximately 125 and 250 pmoles 14C-serotonin/mg protein, respectively, in 3 hours. Imipramine (10-4M) reduced uptake for both cell groups. Cold (4 degrees C) and metabolic inhibitors sharply reduced serotonin uptake by both freshly isolated and cultured endothelial cells. Ouabain (10-5M) almost completely blocked serotonin transport. Six analogues of serotonin at concentrations ten times above experimental serotonin concentrations did not affect serotonin transport in the cultured endothelial cells but did reduce it in the freshly isolated endothelial cells by 50%. The data on transport suggest that serotonin uptake is not unique to pulmonary endothelium, as has been suggested previously. In addition, using cultured indothelial cells to study serotonin transport is compatible with using other serotonin model systems such as platelets, lung, or brain. Lastly, serotonin uptake by endothelial cells may involve an active transport mechanism similar to that described for the pulmonary circulation, platelets, and insect salivary glands. (+info)
Formation of indoleacetic acid by intestinal anaerobes.
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Indoleacetic acid was produced from tryptophan by only three of 23 intestinal anaerobes studied. Evidence is presented to show that the formation of indoleacetic acid proceeds through the intermediate, indolepyruvic acid, via transamination with alpha-ketoglutarate rather than by tryptamine pathway. (+info)
Quantitative gas-liquid chromatography of iproniazid and iproclozide.
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Analytically packed columns prepared with Versamid-930, Versamid-900, XE-60, and OV-225 as stationary phases were examined for quantitative gas-liquid chromatography of the potent monamine oxydase inhibitor (MAOI) drugs iproniazid and iproclozide. With the aid of chemically related substances as internal standards, response ratios were determined and linearities calculated by regression analysis. Using the 2-butyl analogs of compounds all four column systems permit quantitation of iproniazid and iproclozide with a percent standard deviation sigmaK of about 1% or less. (+info)
Drug-induced changes in brain acetylcholine.
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In rats, drug-induced depression of the central nervous system has been shown generally to be associated with an elevation in level of total acetylcholine in the brain. This generalization held true for a wide variety of depressant drugs with one notable exception: the subacute administration of reserpine, with which there was an increase in cerebral acetylcholine after the first dose, but a return to normal levels after subsequent doses, despite continued depression of the animals. Reduction in the level of total acetylcholine in the brain followed the administration of certain convulsants (pentylenetetrazole and 3,5-dimethylbutylethylbarbiturate); but no change was seen after the administration of several mildly exciting agents. The notable exceptions to this generalization were atropine and scopolamine, which significantly lowered brain acetylcholine in doses producing mild excitation in only some of the animals and no gross manifestations in the rest. (+info)
Noradrenaline content in the heart and spleen of the mouse under normal conditions and after administration of some drugs.
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The noradrenaline content of the heart and spleen was investigated in normal mice and in mice treated with drugs. A modification of the methods of Bertler, Carlsson & Rosengren (1958) was used for extraction, and of v. Euler & Floding (1955) for fluorimetric estimation of the amine. In normal mice the mean noradrenaline content of the heart was 0.55 mug/g and that of the spleen 0.26 mug/g fresh tissue. Iproniazid (100 mg/kg), nicotine (0.1 mg/kg) and histamine (0.5 mg/kg), given 1 and 3 hr before killing the mice, did not significantly change the concentration of noradrenaline in the heart. Neither did nicotine and histamine, administered 1 hr before death, significantly alter the noradrenaline content of the spleen. The rapid changes in the catechol amine content of mouse tissues reported with these drugs by De Schaepdryver & Preziosi (1959) were not observed. In contrast, reserpine (2.5 mg/kg), methyl reserpate methyl ether (1 mg/kg), and methyl 18-epireserpate methyl ether (2 mg/kg) caused severe depletion of noradrenaline from the heart and spleen of the mice. (+info)
Effect of antisympathomimetic drugs on the plasma concentrations of catechol amines.
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Intravenous injection of phenoxybenzamine, choline 2,6-xylyl ether bromide (xylocholine, TM 10), piperoxane or dihydroergotamine increases the vasopressor activity of blood plasma, collected from cats under chloralose anaesthesia. The increased vasopressor activity that follows the administration of piperoxane is due to an increase of adrenaline and noradrenaline in the plasma. Cross-circulation experiments show that catechol amines are liberated from the spleen by piperoxane. (+info)