Liver Of Normal Animals Research Articles

Pharmacokinetics and Disposition of Pipecuronium Bromide in Dogs with and without Ligated Renal Pedicles

The pharmacokinetics of pipecuronium bromide have been studied in anesthetized beagle dogs with and without ligated renal pedicles. A gas chromatographic assay was used to measure the plasma, urine, bile concentrations, and liver content of pipecuronium, the later of which was obtained 8 h after injection. Following an iv bolus injection of 0.1 mg/kg, pipecuronium disappeared from the plasma exponentially with distribution half-lives of 3.9 +/- 1.1 min and 12.7 +/- 9.5 min (mean +/- SD), and elimination half-lives of 44.8 +/- 2.6 min and 196.7 +/- 102.0 min in animals with and without renal pedicle ligation, respectively. Except for the volume of central compartment, all other pharmacokinetic variables differed significantly between the two experimental groups. The elimination half-life was longer (196.7 +/- 102 (SD) vs. 44.8 +/- 2.6 min), plasma clearance slower (5.9 +/- 0.8 ml.kg-1.min-1 vs. 0.9 +/- 0.1 ml.kg-1.min-1) and mean residence time longer (221 +/- 73 vs. 51.1 +/- 1.8 min) in dogs with ligated renal pedicles. Eight hours after injection, the recovery of the parent form of pipecuronium approximated 77% of the administered dose in the urine, 4.5% in the bile, and 3.3% in the liver of normal animals. In animals with ligated renal pedicles 16% of the unchanged pipecuronium was excreted into the bile and 10% of the administered dose was recovered from the liver. Since the total recovery of unaltered pipecuronium approximated 85% of the administered dose in the intact animals, biotransformation seems to play an insignificant role in disposition of this new neuromuscular blocking drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Reduced binding and removal of chylomicron remnants by ethionine-induced premalignant liver†

The suppression of cholesterol synthesis by dietary cholesterol which occurs in the livers of normal animals is absent in hepatomas. This abnormality has been reported to occur in the livers of animals fed hepatocarcinogens, even before there is any histologic evidence of malignancy (premalignant liver). We have proposed, in an earlier publication, that the deletion of feedback inhibition of cholesterol synthesis in malignancy is due, at least in part, to the loss of receptors which bind chylomicron remnants, the lipoprotein particles that transport dietary cholesterol to the liver. This hypothesis was further tested in the premalignant liver model. Rats were fed a diet containing 0.25% of a known hepatic carcinogen, ethionine. After 3 to 5 weeks on this diet, the liver had no histologic evidence of malignancy; the rate of [14C]acetate incorporation into cholesterol by liver homogenates was elevated as compared to that of controls (5.13 +/- 0.70 vs. 0.65 +/- 0.14 nmoles cholesterol per gm per hr), and in contrast to control animals, this was not reduced by the inclusion of 5% cholesterol in the diet for 48 hr before killing. The serum (44.4 +/- 6.3 vs. 51.4 +/- 3.8 mg per 100 ml) and hepatic (15.8 +/- 0.2 vs. 17.0 +/- 0.4 micrograms per mg protein) cholesterol contents were not substantially different in ethionine-fed as compared to control-fed rats. Hepatic cholesterol content increased when cholesterol was included in the diet (15.8 +/- 0.2 to 25.8 +/- 7.3 micrograms per mg protein and 17.0 +/- 0.4 to 36 +/- 3.7 micrograms per mg protein in ethionine-fed and control-fed animals, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

A new detergent for the solubilization of the vitamin K-dependent carboxylation system from liver microsomes: Comparison with triton X-100

A new nondenaturing zwitterion detergent has been used to solubilize the vitamin K-dependent carboxylating system from rat liver microsomes. The optimal conditions for solubilization were 1% 3-[(3-cholamidopropyl)dimethylammonio]-1-propane sulfonate (CHAPS) and 1 m NaCl while maximum carboxylating activity was achieved with 0.5% CHAPS, 0.75 m NaCl for a microsomal protein concentration varying from 7.5 to 10 mg/ml. Using CHAPS, high levels of carboxylase activity can be found not only in liver microsomes from vitamin K-deficient rats, but also in microsomes prepared from the livers of normal animals, normal animals supplemented with vitamin K 1, or vitamin K-deficient animals supplemented with vitamin K 1, while little if any activity is detected after Triton X-100 solubilization of the microsomes of such livers. Thus, the new zwitterion detergent proves to be more effective and less denaturing in solubilizing the vitamin K-dependent carboxylase from rat liver microsomes than other detergents used in this system.

Studies of the absorption, distribution and utilization of a potential new haematimic (I-I-diethyl alpha-alpha-thiabiscyclopentaddienyl-iron) in normal mice and mice with sex-linked anaemia.

Summary. The absorption, distribution and utilization of I‐I'diethyl α‐α′‐thiabis‐cyclopentadienyl‐iron (EX10–478), in which iron is present in a non‐ionized form, was studied in normal mice and mice with sex‐linked anaemia, an X‐linked recessive trait characterized by a defect in the intestinal absorption of ionic iron. Treatment of anaemic mice with intragastric EX10–478 and intraperitoneal iron dextran resulted in a complete cure, whereas intragastric treatment with an equivalent amount of ionic iron had no beneficial effect. Investigations using 59Fe labelled EX 10–478 demonstrated relatively high intestinal iron absorption in both anaemic and normal animals, greater utilization of EX10–478 iron for erythropoiesis in anaemic animals compatible with their known iron deficiency and higher deposition of EX10–478 iron in the livers of normal animals. These results indicate that (a) EX10–478 is well absorbed from the intestine, (b) there is no defect in the absorption of non‐ionized iron in sex‐linked anaemia, (c) EX10–478 iron is readily available for haemoglobin synthesis, (d) the liver is probably the principle iron storage site in the mouse, and (e) EX10–478 is a promising new haematinic and a potentially useful experimental tool for the study of iron metabolism.

Changes in guinea-pig liver heparin and histamine during anaphylaxis.

The heparin content of the guinea-pig liver and its change in anaphylactic shock 5 min after injection of antigen under mepyramine cover was estimated by four methods. In sensitized nonchallenged animals, the following values were obtained: 12.32 ± 2.04 U/g by metachromasia; 9.22 ± 0.14 U/g by ribonuclease inhibition; 4.62 ± 0.24 U/g by histaminase release in guinea pigs; 1.64 ± 0.45 U/g by anticoagulant action. Similar values were given by livers of normal animals injected with either NaCl solution or ovalbumin. After challenging the sensitized animals with 10 mg ovalbumin/kg, a significant decrease of the heparin values by 25–50% occurred. The results were analyzed on the basis of our earlier observation that 50 U bovine heparin/kg produces in normal guinea pigs about the same histaminase release from the liver into the blood as does 10 mg ovalbumin/kg in sensitized animals, whereas 500 U heparin/kg is necessary to exhaust the histaminase store in the liver. It follows that the loss of heparin from the liver in shock is high enough to account for the anaphylactic histaminase release. In contrast to heparin, the histamine content of the liver (perfused with aminoguanidine after removal from the body) was significantly increased in shock 5 min after antigen by a factor of 2 or more. After depletion of the liver histaminase by pretreatment of the animals with heparin, the increase of the histamine content was still higher.

Protection by zinc against cadmium toxicity

Pre-injection of male rats with Zn 2+ (20 μmoles) 24 hr before the administration of Cd 2+ (4 μmoles) partially protects against the changes in weight of the testes that are characteristic of the early stages of Cd 2+-injury. This pre-treatment with Zn 2+ induces the synthesis in the livers of the rats of the Cd 2+-binding protein and, in consequence, Cd 2+ ions accumulate and are thus immobilized more rapidly than in the livers of normal animals. It is probable that this accumulation does not occur simply by replacement of Zn 2+ by Cd 2+ in the pre-synthesized binding protein, but that the synthesis of this protein, when induced by the former cation, is stimulated rapidly and without lag on subsequent administration of the latter.

"Sternzellen" in the liver: perisinusoidal cells with special reference to storage of vitamin A.

AbstractThe “Sternzellen” (von Kupffer, 1876) in the liver of normal animals and of those injected with excess vitamin A were examined with the light and electron microscopes. These cells were stellate perisinusoidal cells located in the space of Disse and were separated from the sinusoidal lumen by the endothelium. Their cytoplasm contained a number of lipid droplets which reacted intensely with gold chloride. These lipid droplets imparted intense vitamin A fluorescence under the fluorescence microscope. Following the administration of excess vitamin A, these lipid droplets increased remarkably. The “Sternzellen” were identical with cells described as “interstitial” or “fat‐storing” cells by others, and were quite different from the so‐called Kupffer cells of the liver reticulo‐endothelial system.

Tyrosine α ketoglutarate transaminase in the liver of rats with intra-uterine growth retardation

The postnatal induction of TKT in the liver of rats submitted to intra-uterine growth retardation (I. U. G. R.) is much more greater than in the liver of normal animals. This striking rise in activity, seems to be related to the low blood glucose levels found in the I. U. G. R. animals. However glucagon injections to I. U. G. R. fetuses are not so efficient as in the case of the controls.

Decreased uroporphyrinogen decarboxylase activity in ‘experimental symptomatic porphyria’

An experimental porphyria resembling human acquired symptomatic porphyria from the biochemical viewpoint was induced in rats by prior iron overload followed by the feeding of hexachlorobenzene (HCB). The characteristic accumulation of 8- and 7-carboxyl porphyrins in the livers of these animals suggested a possible defect of decarboxylation of uroporphyrinogen. Uroporphyrinogen decarboxylase activity was readily demonstrable in the livers of normal animals but undetectable in the iron-loaded porphyric animals. In view of the biochemical resemblance between this experimental model and the human disease, it is considered probable that a similar defect exists in the livers of patients with symptomatic porphyria.

Tissue-specific mitotic inhibition in the kidneys of embryonic grafts and partially nephrectomized host Xenopus laevis

Immature Xenopus laevis were unilaterally nephrectomized and implanted subcutaneously with stage 38 (prefeeding) larvae. Rat kidney extract was injected 8 and 16 days after the operation and the mitotic incidence (MI) in the host and implant tissues was measured by the colcemid metaphase arrest technique. The MI in the kidney of nephrectomized hosts was higher than normal at 8 days but had returned to the control level at 16 days. Injection of kidney extract inhibited mitosis in the host kidney both at 8 and 16 days after partial nephrectomy. The MI of implant pronephros was higher in nephrectomized than in control hosts both at 8 and 16 days. Injection of kidney extract into nephrectomized hosts inhibited mitosis in the implant pronephros both at 8 and 16 days. Neither host nephrectomy nor injection of kidney extract had any effect on the MI in the epidermis of the implants. Unoperated immature Xenopus were injected with rat kidney or liver extracts. Kidney extract inhibited mitosis in the kidney but not in the liver, while liver extract inhibited mitosis in the liver but not in the kidney. The rate of mitosis in the kidney and liver of normal animals may be controlled by tissuespecific inhibitors of cell division.

Effect of adrenalectomy on amino acid incorporation into protein by cell-free preparation from liver and kidney of rats at various time after the operation

Amino acid incorporation into protein by liver ribonucleoprotein particles and kidney microsomes, obtained from normal and adrenalectomized rats, was investigated. The liver and kidney particles were prepared at various times, ranging from 3 h to 31 days after adrenalectomy. The 14C-incorporating activity of liver particles from adrenalectomized rats was greater than that observed with particles from liver of normal animals up to 15 days after adrenalectomy; at 21 and 31 days after the operation the liver particles showed an activity 60 and 80 %, respectively, of that of the control group. Microsomes from kidney of adrenalectomized rats demonstrated an incorporating activity higher than that of the microsomes from kidney of normal animals at all the times investigated; a sharp increase was observed at 21 and 31 days after adrenalectomy, when the activity of the liver particles was low. A correlation was established between incorporating activity of liver and kidney particles; to an increase or decrease in the activity of the particles from the liver corresponded a decrease or an increase, respectively, in the activity of the kidney microsomes. The 14C-incorporating activity of both liver and kidney particles was directly proportional to the ratio of μg RNA to mg protein in these particles up to 15 days after adrenalectomy, deviations occurring at more prolonged time after the operation.

The influence of adrenalectomy and of cortisone treatment on arginase and esterase activities in liver tissue

1. 1. Liver biopsies were carried out on fed adult rats before and after adrenalectomy and before and after cortisone injections. The effect of this treatment on the levels of hepatic arginase and esterase in extracts prepared from the excised tissue was investigated. 2. 2. Adrenalectomy caused a substantial reduction in the arginase activity which was restored to the normal level after cortisone injections. The latter also stimulated the arginase activity in the liver of normal animals. 3. 3. A slight fall in arginase activity was also observed in control experiments in which biopsies were carried out without previous adrenalectomy or hormone treatment. The fall was due to the repeated removal of very, small amounts of tissue during biopsies, but not to operational shock. When extensive liver damage was inflicted deliberately, the arginase activity was subsequently stimulated. This was interpreted as being the result of extensive regenerating processes in the liver tissue, and is in accordance with similar observations by other workers. 4. 4. The influence of cortisone on hepatic arginase is discussed in the light of the well known stimulating effect of adrenal hormones on tissue metabolism in general. 5. 5. The hepatic esterase activity was also greatly reduced after adrenalectomy, but only minor changes were observed after cortisone injections.