Distribution of local anesthetics: accumulation in some endocrine polypeptide-hormone producing cell systems.

1 After the injection of labelled procaine and lidocaine in mice, the location and concentration of radioactivity was demonstrated by autoradiographical methods.2 An accumulation in some endocrine cells such as the pancreatic islets, the hypophysis, the adrenal medulla and certain cells of the thyroid (probably representing the calcitonin-producing parafollicular cells) was shown.3 After the injection of [(14)C]-procaine in chicks, an accumulation of radioactivity was observed in the ultimobranchial gland (which produces calcitonin in birds), but not in the thyroid.4 Radioactivity was also shown to be strongly concentrated in structures containing melanin, such as the pigment of the eye, skin and hair and in some organs involved in the metabolism and excretion of these drugs.

Uptake and distribution of daunorubicin and daunorubicin-DNA complex in mice as studied by whole-body autoradiography and liquid chromatography.

The tissue distribution of daunorubicin (D) and daunorubicin-DNA complex (D-DNA) was studied in mice by means of whole-body autoradiography (WBA) and high-performance liquid chromatography (HPLC). A higher accumulation of radioactivity in the blood after 1 min and a lower initial accumulation in the cardiac muscle were found after administration of 3H-D-DNA than after the infection of free drug. Comparative studies of plasma levels of daunorubicin and daunorubicinol (DOH) in D- and D-DNA-treated animals by HPLC showed that the initial differences were negligible from 2 h onward. A rapid accumulation of D in bone marrow occurred in both D- and D-DNA-treated mice. D reached its maximum level after 1 h and was almost constant for 12 h. A new WBA finding was a rapid and specific accumulation of radioactivity in the pituitary gland, in the thyroid, and in the pancreatic islets, which might be of some interest in consideration of possible late endocrine side effects of anthraquinone glycoside therapy.

A comparison of the regional ontogenesis of nicotine- and muscarine-like binding sites in mouse brain.

The postnatal development of the cholinergic neurotransmitter system was studied in the cortex, hippocampus, midbrain and cerebellum of 3-, 7-, 12-, 17- and 30-day-old NMRI mice. The concentration of muscarine-like binding sites determined with [(3)H]quinuclidinyl benzilate as a ligand increased progressively with age. A similar developmental pattern was found for the activity of a presynaptic marker, choline acetyltransferase (ChAT). When expressed as a percentage of the values for 30-day-old mice, however, the muscarine-like receptors were parallel but preceding the development of ChAT in all the brain regions studied. The concentration of nicotine-like binding sites studied with [(3)H]α-bungaro-toxin as a ligand gradually increased with age in the cortex, hippocampus and midbrain, with a peak between days 7 and 12, followed by a decrease towards day 30. With [(3)H]tubocurarine as a ligand, on the other hand, the concentration of nicotine-like binding sites was in general high at 3 days and gradually decreased with age, suggesting that different subpopulations of nicotine-like receptors might be determined when the two ligands are used.

Persistence of 2,3,6-substituted pentachlorobiphenyls in the lung parenchyma: a new structure-dependent tissue localization of polychlorinated biphenyls in mice.

Whole body autoradiograms of mice injected with 2,2',3,3',6-[14C]pentachlorobiphenyl (I), 2,3,3',4',6-[14C]pentachlorobiphenyl (II), 2,2',3,5',6-[14C]pentachlorobiphenyl (III) and 2,3',4,5,5'-[14C]pentachlorobiphenyl (IV) showed a specific accumulation of I-III in the lung parenchyma, whereas IV did not accumulate in the lung tissue. The results suggest that chlorobiphenyls with chlorine atoms in the positions 2,3,6 possess a specific affinity for the lung parenchyma. These chlorobiphenyls differ in chemical structure from those which are accumulated in the bronchial mucosa and those which are not taken up in the respiratory tract. The importance of in vivo metabolism in the determination of structure activity relationships is stressed.

Studies on the tissue disposition and fate of [14C]toxaphene in Japanese quail.

The disposition and the fate of a [14C]toxaphene preparation was studied in adult and juvenile female Japanese quail. The distribution of [14C]toxaphene in the body is dominated by high concentrations of radioactivity in the adipose tissue and the egg yolk, and, especially in juvenile birds, in the bone marrow. The [14C]toxaphene compounds present in the fat tend to be less polar than the parent [14C]toxaphene. More than half of the radioactive dose is excreted via the droppings, eggs, and preen gland within a few days, with biliary excretion playing a major role. The main part of the radioactivity in feces and urine consists of water soluble compounds, a part of which is indicated to be glucuronide and sulfate conjugates, but other metabolites are probably also present. A possible connection between the toxaphene residues in the bone and the known toxaphene induced osteomalacia in birds is discussed.

Effects of dietary sodium selenite supplementation on salicylate-induced embryo- and fetotoxicity in the rat.

The effects of dietary supplementation with sodium selenite (3.0 or 4.5 ppm Se) for 8 weeks prior to and throughout gestation on sodium salicylate induced embryo- and fetotoxicity (resorptions, fetal deaths, malformations, fetal weight reduction) have been studied in the rat. Salicylate was administered either as daily intragastric bolus doses of 250 mg/kg on gestation days 6-13 (maternal peak and trough salicylate levels of 222-120 micrograms/ml whole-blood) or via constant rate intravenous infusion of 150 mg/kg/day on the same gestation days via implanted osmotic minipumps (stable average maternal blood salicylate level of 120 micrograms/ml = human antirheumatic concentration). Both gavage and infusion of salicylate resulted in an increase of resorptions and fetal deaths as well as a decrease of fetal body weights. Gavage with salicylate also produced about 50% malformed fetuses. Selenite did not protect against the embryotoxic effects of salicylate administered as intragastric bolus doses. However, selenite was found to significantly increase fetal survival rate in the infusion experiment, although it did not counteract the decrease of fetal body weight. In animals fed selenite only, no negative effects on fetal body development were noted. The protective effect of selenite against salicylate induced embryotoxicity is difficult to explain, since very little is known about the mechanisms of salicylate embryotoxicity and the biological effects of selenium. However, an interaction between selenium, via glutathione peroxidase, and salicylate at the level of prostaglandin synthesis could be possible.

A muscarinic receptor type in human lymphocytes: a comparison of 3H-QNB binding to intact lymphocytes and lysed lymphocyte membranes.

Human blood lymphocytes from normal blood donors exhibited specific binding of the muscarinic antagonist 3H-quinuclidinyl benzilate (3H-QNB). The 3H-QNB binding to intact viable lymphocytes as well as to lysed lymphocyte membranes "P2" was saturable and displaceable by both muscarinic agonists and antagonists. For the lysed lymphocyte membranes "P2" a single binding site with a Bmax of 109 pmol/g protein and a Kd of 15 nM was obtained. Intact viable lymphocytes also showed one binding site with a Kd of 24 nM and a Bmax of 1556 pmol/g protein. The higher Bmax value might be explained in terms of uptake of the ligand when using intact cells or through loss of binding sites when using lysed lymphocyte membranes "P2". IC50 values were lower by a factor of 10(2) for atropine and scopolamine and by 10(4) for pirenzepine when lysed lymphocyte membranes "P2" were used instead of intact viable lymphocytes.

Effects of dietary selenium compounds on benzo (a)-pyrene-induced forestomach tumours and whole-blood glutathione peroxidase activities in C3H mice.

Selenium (Se) compounds have shown an inhibitory effect on chemically induced tumours in several laboratory models and there is an inverse epidemiological relationship between Se status and certain types of cancer. Little is known about the influence of Se on the development of stomach cancer. Three different forms of dietary Se, selenomethionine, sodium selenite, and high-selenium yeast were investigated as possible inhibitors of benzo(a)pyrene-induced forestomach tumours in mice. The effects of sodium selenite in combination with vitamin E, and of Se-deficiency were also studied. None of the dietary modifications had any effect on tumour incidence or number. Marked elevations of whole-blood glutathione peroxidase (GSH-Px) activities were observed in animals supplemented with all Se-compounds. High-selenium yeast caused the largest increase of GSH-Px activity followed by sodium selenite and selenomethionine. The results indicate that the inhibitory effect of Se on carcinogenesis may be specific with respect to organ site or tumour cell examined.

Distribution of [1-14C] acrylonitrile in rat and monkey.

The distribution of [1-14C] acrylonitrile (ACN) in rat and monkey has been studied by whole-body autoradiography, after being administered orally and intravenously to rats and orally to monkeys. Uptake of radioactivity was seen in the blood, liver, kidney, lung, adrenal cortex and stomach mucosa.

Toxaphene: accumulation in the adrenal cortex and effect on ACTH-stimulated corticosteroid synthesis in the rat.

Uptake and distribution of [14C]toxaphene was studied in the adrenals of rats using whole-body autoradiography. An accumulation of radioactivity was seen in the adrenal cortex (zona fasciculata) 1-24 h after a single gavage of [14C]toxaphene (16 mg/kg b.w.). In in vitro studies toxaphene was found to inhibit ACTH-stimulated corticosterone synthesis in the cultured rat adrenocortical cells (IC50 2.8 X 10(-5) M). Moderate but significant inhibition (P less than 0.001) of ACTH-stimulated corticosterone synthesis was also observed in the adrenocortical cells isolated from rats after a prolonged exposure (5 weeks) to low levels (1.2 ppm) of toxaphene in feed. The results indicate a direct adrenotoxic effect of toxaphene.