Aminoaciduria and proteinuria in rats after a single intraperitoneal injection of Ni(II).

Proteinuria was found in Fischer female rats after a single ip injection of NiCl₂ in dosages from 34 to 85 μmol/kg (2–5 mg Ni/kg). Generalized α-aminoaciduria was found after a single ip injection of NiCl₂ in dosages of 68 and 85 μmol/kg (4 and 5 mg Ni/kg). Amino acids in plasma were normal or slightly diminished from 1 to 48 hr after injection of Ni(II). Electron microscopy of kidneys of five rats at 48 hr after Ni(II) (68 μmol/kg) consistently revealed fusion of foot processes of glomerular epithelial cells. Focal tubular necrosis was present in the kidney of one of these rats. This study demonstrates that toxic nephrophathy with aminoaciduria and proteinuria develops in rats after ip Ni(II). Amino acid and protein excretions consistently returned to normal by Day 5.     

Effects of Ni(II) upon plasma glucagon and glucose in rats.

Plasma glucagon and glucose concentrations were measured in fasting Fischer rats after administration of Ni(II) as NiCl₂ in ip dosage of 34 or 68 μmol/kg. Injection of Ni(II) produced prompt increases in plasma glucagon and glucose concentrations. Thus, at 0.5 hr after Ni(II) (68 μmol/kg), plasma glucagon concentrations averaged 0.75 ± 0.24 ng/ml (vs 0.20 ± 0.05 in control rats, p < 0.001), and plasma glucose concentrations averaged 236 ± 17 mg/dl (vs 137 ± 11 in control rats, p < 0.001). Plasma concentrations of glucagon and glucose in Ni(II)-treated rats returned to control values within 2–4 hr following the ip injection. These findings suggest that hyperglucagonemia may be responsible for the acute hyperglycemic response to Ni(II).     

The effects of phenobarbital, atropine, L-alpha-methyldopa, and DL-propranolol on dieldrin-induced hyperglycemia in the adult rat

The hyperglycemic response of adult male Wistar rats given dieldrin (63 mg/kg, po) and either phenobarbital (40 mg/kg, ip), atropine (4 mg/kg, sc), L-alpha-methyldopa (200 mg/kg, ip), or DL-propranolol (8 mg/kg, sc) was studied. The hyperglycemia was maximal (73% above control values) 2 hr after exposure to dieldrin alone. Phenobarbital reduced the hyperglycemia by 41% and abolished dieldrin-induced convulsions. It also prevented the increases that dieldrin causes in hepatic phosphoenolpyruvate carboxykinase (PEPCK) activity. These results suggest that the dieldrin-induced hyperglycemia is mediated via the CNS. Atropine prevented the hyperglycemia for 2 hr and delayed the attainment of maximal glucose concentrations for another 2 hr. However, additional atropine 4, 8, 12, and 18 hr after the dieldrin had no effect. Atropine also increased (125%) the time to the onset of dieldrin-induced convulsions. It did not alter hepatic PEPCK activity. L-alpha-Methyldopa decreased (24%) the hyperglycemic response in the first 2 hr after dieldrin treatment. It caused similar reductions in blood glucose when given during the peak hyperglycemic response. L-alpha-Methyldopa also reduced (49%) the dieldrin-effected increase in hepatic PEPCK activity. DL-Propranolol did not alter the effects of dieldrin. Thus these data suggest that the dieldrin-induced hyperglycemia is mediated by the CNS, primarily via enhanced cholinergic activity and secondarily by increased alpha-adrenergic activity. It is suggested that the pancreas responds to the cholinergic outflow by increasing the secretion of glucagon while simultaneously responding to the alpha-adrenergic outflow by decreasing insulin secretion.     

Placental transfer and body distribution of nickel chloride in pregnant mice

Placental transfer and body distribution of NiCl₂ were studied in pregnant mice (ICR strain, 12–14 weeks old). A single injection of NiCl₂ (4.6 mg/kg as Ni ip) was administered on the 16th day of gestation. Animals were killed at intervals of 2, 4, 6, 8, 10, 24, 30, and 48 hr after the injection and tissues were obtained for measurement of nickel concentration. Concentration of nickel in blood and placentas were found to be at maximum level (19.8 and 3.9 μg/g) 2 hr after injection, and those in liver, spleens, and kidneys reached maximum levels of 4.9, 1.3, and 56.2 μg/g, respectively, 4 hr after injection. Maximum concentration in fetal tissues (1.1 μg/g) was reached 8 hr after injection, and a slight gradual decrease was observed during 24 hr. Thereafter, there was a rapid decrease. The relative concentrations of Ni in blood, organs, and tissues of pregnant mice at 24 hr after injection were found in order from highest to lowest concentration: Kidneys > blood > placentas > fetuses ? liver > spleen. It is estimated that the Ni will be excreted in about 42 to 84 hr after injection from the calculated biological half-times.     

Effects of triethylenetetramine upon the metabolism and toxicity of 63NiCl2 in rats

Triethylenetetramine (TETA, 0.75 mmol/kg, im) was administered to Fischer rats immediately prior to ⁶³NiCl₂ (0.068 or 0.10 mmol/kg, ip or im) to determine (a) effects of TETA upon ⁶³Ni-kinetics, and (b) antidotal effects of TETA upon Ni-induced nephrotoxicity and hyperglycemia. TETA markedly reduced plasma ⁶³Ni concentrations and greatly increased urine ⁶³Ni excretion during 6 hr after injection of ⁶³NiCl₂, compared to values in control rats that received only ⁶³NiCl₂. In rats killed 6 hr after injections of TETA and ⁶³NiCl₂, ⁶³Ni concentrations in liver, kidney, spleen, lung, and heart averaged 3.4, 0.72, 0.27, 0.22, and 0.12 times corresponding ⁶³Ni concentrations in organs from control rats that received only ⁶³NiCl₂. The results supported the hypothesis that combined administration of TETA and ⁶³NiCl₂ resulted in partition of the body pool of ⁶³Ni between two major ⁶³Ni-components: (a) ⁶³Ni-TETA complex, and (b) nonchelated-⁶³Ni, and that each ⁶³Ni-component was eliminated from plasma according to its respective clearance. The renal clearance of ⁶³Ni-TETA complex was estimated to be >20 times that of nonchelated-⁶³Ni. Administration of TETA substantially reduced Ni-induced proteinuria and aminoaciduria. TETA did not prevent Ni-induced hyperglycemia and hyperglucagonemia, but TETA did partially inhibit Ni-induced hyperinsulinemia.     

Chelation of lead by dimercaptopropane sulfonate and a possible diagnostic use

The mobilization of lead (Pb) from Pb-exposed rats was examined following administration of dimercaptopropane sulfonate (DMPS). A dose-response study showed that the highest dose of DMPS (200 μmol/kg, ip) removed Pb from kidneys, liver, and bone, while the lower doses (25 and 50 μmol/kg) chelated Pb only from the kidneys. In experiments where DMPS was repeatedly injected to Pb-exposed rats, the maximum urinary excretion of Pb was observed within 24 hr after the first injection, with little effect in subsequent injections. Discontinuation of DMPS after the first injection (at a dose of 50 μmol DMPS/kg) caused renal Pb levels to increase until further injection of DMPS, several days later, which again mobilized Pb only from the kidneys. A single oral administration of 150 μmol DMPS/kg (a dose adjusted for specific chelation from the kidney) to rats, previously exposed to different doses of Pb resulted in a significant decrease of renal Pb in groups injected with more than 0.5 mg Pb/kg. A linear relationship was observed between renal Pb burden and urinary Pb excretion following chelation (r = 0.94, p < 0.01). Thus, the specific removal of Pb from the kidney by DMPS treatment suggests a potential use of DMPS, a relatively nontoxic drug, for the estimation of renal Pb burden and also for treatment of Pb poisoning. Unlike other chelating agents, DMPS can be administered orally.     

Repeated administration of triiodothyronine (T3) to rats enhances nigrostriatal and mesolimbic dopaminergic behavioural responses

A once daily injection to rats of triiodothyronine (T₃; 100 μg/kg s.c.) for 10 days enhanced the locomotor responses of rats pretreated with tranylcypromine (5 mg/kg) to an injection into the nucleus accumbens of dopamine (5 μg bilaterally), when tested 24 hr after the last T₃ administration. This treatment did not, however, alter the control responses of tranylcypromine-pretrealed rats to injection of saline (1 μl bilaterally). Injection of T₃ for 10 days enhanced the circling responses of unilateral nigrostriatal-lesioned rats to apomorphine (0.5 mg/kg) but not to methamphetamine (0.5 mg/kg). The probable explanation for the latter result was the finding that repeated T₃ administration lowered basal striatal dopamine concentrations. The treatment also produced a trend towards reduced dopamine concentrations in the n. accumbens, although the difference did not reach statistical significance. These data suggest that repeated T₃ injection causes an increased post-synaptic function of both the nigrostriatal and mesolimbic dopamine systems in rat brain.     

Decrease in blood coagulation factors II (prothrombin), VII, IX and X in the rat after a single oral dose of butylated hydroxytoluene

Male Sprague-Dawley rats were given butylated hydroxytoluene (BHT) in a dose of 800 mg/kg body weight orally, and 0.5-72 hr later plasma concentrations of factors II, VII, IX and X and hepatic levels of BHT and BHT quinone methide (2,6-di-tert-butyl-4-methylene-2,5-cyclohexadienone) were determined. Levels of factors II, VII, X and IX were reduced 36-60 hr after BHT treatment, but by 72 hr, those most affected (VII and IX) showed some recovery and X had returned to normal. Hepatic levels of BHT reached a maximum 3 hr (a major peak) and 24 hr after BHT dosing and BHT quinone methide reached a maximum at 6 and 24 hr (a major peak). In rats given BHT orally in doses of 200, 400 and 800 mg/kg, factors II, VII and X decreased after 48 hr only in rats given the highest dosage, but factor IX was more susceptible to BHT and showed a dose-dependent decrease. Phylloquinone (1 mg/rat) injected ip 24 hr after the administration of 800 mg BHT/kg maintained normal levels of factors VII and X and an almost normal level of factor IX, but had little effect on the level of factor II. In studies of the effects of drug-metabolizing-enzyme modifiers, neither ip pretreatment with 75 mg phenobarbital sodium/kg for 3 days nor the feeding of 1% cysteine in the diet throughout the experiment prevented the decrease in vitamin-K-dependent factors by 800 mg BHT/kg, but 2-day ip pretreatment with 60 mg cobaltous chloride/kg/day maintained normal levels of factors II and VII and reduced the BHT effect on factors IX and X. SKF 525A (50 mg/kg) injected ip either 30 min before or 12 hr after BHT treatment partially prevented the decrease in factors II, VII and X, or in all four factors, respectively. Thus the decrease in vitamin K-dependent factors may be the same with a single oral dose of BHT as with dietary BHT, and the anticoagulant effect may require the metabolic activation of BHT.     

Protection of carbon tetrachloride-induced hepatotoxicity by zinc: role of metallothionein

The dose-dependent release of alanine aminotransferase and aspartate aminotransferase into plasma 24 hr following various doses of CCl₄ (ip) was markedly lower in rats pretreated for 3 days with zinc chloride (150 μmol/kg/day) than in control rats. Although this dose of zinc produced a 34% decrease in hepatic concentration of cytochrome P-450 and a 50% decrease in binding of ¹⁴C derived from ¹⁴CCl₄ to hepatic microsomal protein and lipid in vitro, prior treatment with a single injection of zinc (250 μmol/kg) resulted in protection against CCl₄ toxicity without changing P-450 concentrations or ¹⁴C binding. Administration of a single dose (250 μmol/kg) of zinc or pretreatment on 3 consecutive days with 150 μmol/kg zinc produced a 700 or 1900% increase in hepatic concentration of metallothionein (MT), respectively. Following administration of ¹⁴CCl₄ to zinc-treated rats, radioactivity was present in the same elution volume as MT following gel filtration (G-75) of liver cytosol. This suggests that MT may protect against CCl₄-induced liver damage by sequestering reactive metabolites of CCl₄.     

Embryotoxicity and fetal toxicity of nickel in rats

Embryotoxicity and fetal toxicity of nickel chloride (NiCl₂) and nickel subsulfide (Ni₃S₂) were studied in Fischer rats. Injection of NiCl₂ (16 mg of Ni/kg, im) on Day 8 of gestation reduced the mean number of liver pups per dam and resulted in diminished body weights of fetuses on Day 20 of gestation and of weanlings at 4 to 8 weeks after birth. Injection of Ni₃S₂ (80 mg of Ni/kg, im) on Day 6 of gestation reduced the mean number of live pups per dam. No congenital anomalies were found in fetuses from any Ni-treated dams, including dams that received 10 im injections of NiCl₂ (2 mg of Ni/kg, twice daily, on Days 6–10 of gestation). ⁶³NiCl₂ (12 mg of Ni/kg, im) was administered to a group of nonpregnant female rats and to groups of pregnant rats on Day 8 or 18 of gestation. After 24 hr, the relative concentrations of ⁶³Ni in tissues were: kidney > serum > adrenal ? lung ? ovary > spleen ? heart ? liver > skeletal muscle. Pituitary ⁶³Ni concentrations were much higher in pregnant rats than in nonpregnant females. ⁶³Ni concentrations in products of conception (embryos and embryonic membranes) on Day 9 and in placentas on Day 19 were equivalent to ⁶³Ni concentrations in adrenal, lung, and ovary tissues of the dams. Autoradiography of fetuses and placentas on Day 19 of gestation showed ⁶³Ni localization in fetal urinary bladders and in the basal laminae and yolk sacs of the placentas. These studies show (a) that im injection of NiCl₂ and Ni₃S₂ during early gestation causes embryonic mortality at dosages that do not cause maternal mortality, and (b) that ⁶³Ni(II) can cross the feto-maternal barriers and enter the fetuses during late gestation.     

Selenite-induced protection of bromobenzene hepatotoxicity in male rats

Acute treatment with sodium selenite effectively reduces bromobenzene hepatotoxicity in male, Sprague-Dawley rats. Hepatocellular damage was ameliorated as shown by marked decreases in plasma alanine and aspartate aminotransferase (ALT and AST) activities. A single dose of selenite (12.5 or 30 μmol Se/kg, ip) was administered to rats at 4, 24, 48, or 72 hr before injection of bromobenzene (7.5 mmol/kg, ip). Plasma ALT and AST activities and hepatic glutathione (GSH) content were measured 24 hr after bromobenzene treatment. As the length of time of selenite pretreatment increased, the extent of reduction of bromobenzene-induced elevation in plasma enzyme activities by selenite was enhanced, and generally, in a dose-related manner with optimal protection occurring in rats pretreated 72 hr prior with selenite. However, depletion of liver GSH by bromobenzene was not affected by selenite treatment. Hepatic GSH levels and GSH detoxication enzyme activities were measured at various intervals in rats treated with selenite alone. Selenite increased hepatic GSH content 20 to 25% at both 24 and 48 hr after injection, with a return to GSH control levels at 72 hr. Selenite treatment produced slight decreases in GSH peroxidase activity but did not alter GSH S-transferase activity. These studies suggest that the reduction of bromobenzene hepatotoxicity by selenite does not involve alterations in the activity of hepatic GSH detoxication enzymes; however, the data suggest that factors in addition to selenite-induced changes in hepatic glutathione levels are also involved.     

Effect of sodium dichromate on carbohydrate metabolism

Subcutaneous injection of sodium dichromate into male Sprague-Dawley rats immediately produced a variety of metabolic changes in a dose-dependent manner. Serum lactate and glucose were significantly increased after dichromate treatment, reaching maximum levels at 15 and 30 min, respectively. Then, the toxicity progressively diminished. In contrast, a steady increase in blood urea nitrogen (BUN) concentration was caused by dichromate, reaching maximum levels at 60 min after the administration; elevated BUN levels were sustained for several hours thereafter. Unlike KCN (5 mg/kg, ip) and As2O3 (5 mg/kg, ip), dichromate rapidly decreased serum insulin within 15 min after intoxication in doses of 20 and 40 mg/kg; hypoinsulinemia lasted 60 min. However, insulin levels returned to the normal range at 120 min after treatment. Dichromate-induced metabolic disturbance was also observed in the 24 hr-fasted rats, the response of which was similar to normal rats except for later hyperglycemia. In both cases, the duration time was short (30 to 60 min). Adrenalectomy and insulin pretreatment had no effect on dichromate-induced hyperglycemia. These results suggest that dichromate-induced metabolic disturbance results from the concomitant effects of a sudden decrease in serum insulin level and its direct inhibitory effect on carbohydrate metabolism. In addition, the characteristic biphasic pattern of metabolic disturbance might be related to metabolic fate of dichromate in vivo.     

Hyperglycemia produced in mice by administration of acetazolamide and diphenylhydantoin

Isolated mouse islets exposed to 3 mM glucose released an increased amount of insulin in the presence of acetazolamide (AZM) (10 mM) and diphenylhydantoin (DPH) (0.35 or 3.5 mM), whereas insulin secretion due to 20 mM glucose was decreased in the presence of AZM (10 mM) and DPH (0.35, 0.70 or 3.5 mM). The serum insulin concentration was increased 1 h after AZM injection, but was not significantly altered 1 h after combined administration of AZM and DPH. A moderate transient hyperglycemia was found 1 and 2 h after DPH injection (100 mg/kg b.w.) in fed mice, and a slight, transient hyperglycemic response was observed 24 h after administration of AZM (1.5 g/kg b.w.) to fed mice. A steadily increasing, marked hyperglycemia was seen in both fed and starved mice when AZM was given shortly before or after DPH. All animals subjected to this kind of treatment died within 48 h after the injections. Ketones were found in the urine and serum of the hyperglycemic animals, and the hyperglycemia was abolished and the survival of the animals was prolonged by insulin administration, suggesting that ketoacidosis contributed to the death. Light microscopy disclosed degeneration and necrosis of some B-cells, and occasionally insulitis after combined treatment with AZM and DPH. Pretreatment with AZM inhibited the hyperglycemic response to p-hydroxymercuribenzoate in fed mice, but did not affect the hyperglycemic response of fed mice to D-mannoheptulose. The findings indicate that AZM and DPH, when given to mice in combination and in sufficient amount, cause impaired B-cell function with an inhibited glucose-induced insulin release and a severe, fatal hyperglycemia. The B-cell changes are belived to be due to intracellular ionic alterations.     

Effects of tetracycline on ultrastructure and lipoprotein secretion in the rat hepatocyte

Fat droplets, 0.1–0.5 μm, accumulated in the space of Disse of hepatocytes in rats treated ip with 300 mg/kg of tetracycline hydrochloride. This change occurred in both pregnant and unbred females and in males but was not observed in similar rats treated with 100 mg/kg which showed typical steatosis induced by tetracycline. Ultrastructural changes in mitochondria, rough and smooth endoplasmic reticulum (SER) were similar to those previously reported. Uptake of iv administered palmitic [9-10-³H]acid in rats treated with 300 mg/kg was not appreciably impaired. One hour after an injection of 300 mg/kg, the antibiotic concentration was 10 times greater in the liver than in the serum. From 1 to 6 hr the concentrations increased from roughly 300 to 800 μg/g of liver. In rats treated with 100 mg/kg, no concentrations above 200 μg/g were observed during a 48-hr postinjection period. Under in vitro conditions, tetracycline complexed with lipoprotein in a precipitate when a concentration greater than 200 μg/ml was obtained in rat blood serum. In the hepatocyte of rats treated with 300 mg/kg it was presumed that as the antibiotic concentration rose above 200 μg/g nascent very low density lipoprotein complexed rapidly with it. The complexed lipoprotein was channeled in dilated SER in the manner of liposomes to the sinusoidal surface and discharged from vesicles into the space of Disse. The plasma membrane of the hepatocyte showed loss of microvilli and surface distortion. The space of Disse became distended with insoluble fat droplets from 6 hr to 3 days after injection.     

Influence of chelating agents on the distribution and excretion of cadmium in rats

The effects of the chelating agents CaNa₂-ethylenediaminetetraacetate (EDTA), CaNa₃-diethylenetriaminepentaacetate (DTPA), 2,3-dimercaptosuccinic acid (DMSA), 2,3-dimercaptopropanol (BAL), and 2,3-dimercaptopropane-1-sulfonate (DMPS) and of the lipophilic chelating agents Puchel, Puchel-bisamidocysteineethyl ester (Puch-D), and EDTA-bis-amidocysteineethyl ester (EDTA-D) on the distribution of iv injected Cd were studied in male Sprague-Dawley rats. The chelating agents were injected iv as single doses given 10 sec, 1 hr, or 3 hr after 3 μmol/kg Cd + ^115mCd. When the chelating agents were injected within 10 sec after the metal, all agents reduced the total body cadmium burden by varying extents ranging from 3% of that in untreated control rats after 0.01 mmol BAL/kg to 94% following 0.1 mmol DTPA/kg. When given 1 hr after Cd injection, the efficacy of all the agents tested was markedly reduced or abolished; at this time only Puchel and Puc 3h-D provoked significant reductions in the body burden of Cd by 21 and 32%, respectively. When treatment was delayed until 3 hr after Cd injection, only Puch-D was able to reduce the body and liver burden of the metal by 14 and 9%, respectively. Combined treatment with Puchel + DTPA, BAL + DTPA, or BAL + DMPS did not enhance Cd removal to an extent greater than that expected from the equivalent dose of the more effective agent of that pair alone. Repeated administration of DTPA, 20 × 0.1 mmol/kg, during 4 weeks by ip or po administration of the same dose in the drinking water over 4 weeks, was no more effective than the first dose of the chelating agent alone. Gel chromatographic studies of the distribution of Cd among the proteins of the liver cytosol in treated and untreated animals indicate that neither DTPA nor Puchel was able to release Cd from the metallothionein complex.     

Effect of sertindole on raised mesolimbic dopaminergic activity in the rat

The effect of sertindole in models of mesolimbic dopamine excess in the rat was evaluated. Sertindole (0.0057–0.011 μmol/kg = 2.5–5 μg/kg, sc) and haloperidol (0.13–0.27 μmol/kg = 50–100 μg/kg, ip) inhibited the hyperactivity caused by the acute intra-accumbens injection of amphetamine (20 μg). The administration of sertindole (0.0057–2.8 μmol/kg = 2.5 μg–1.25 mg/kg, sc daily), haloperidol (0.027–0.40 μmol/kg = 10–150 μg/kg, ip bd) or clozapine (15–31 μmol/kg = 5–10 mg/kg, ip, bd) during a 13-day period of dopamine infusion (25 μg/24 h) into the nucleus accumbens reduced the dopamine-induced hyperactivity response to control levels, except at the highest dose which reduced activity to below control levels. Locomotor activity remained at control levels after discontinuing the dopamine/sertindole treatment regimen, whereas discontinuation of the dopamine/haloperidol treatment regimen resulted in rebound hyperactivity. Sertindole (0.0057 μmol/kg = 2.5 μg/kg, sc) given either once daily or once every 2 days prevented the development of hyperactivity in the intra-accumbens dopamine infusion model. One injection given every 4 days failed to modify the response to a dopamine infusion. Sertindole (0.0057 μmol/kg = 2.5 μg/kg, sc daily) inhibited hyperactivity caused by unilateral infusion of dopamine (50 μg/24 h, 13 days) into the left amygdala of rats having right hemispheric dominance (as measured in a turn preference test). In contrast to haloperidol, sertindole failed to initiate circling behaviour following unilateral, intrastriatal injection. In conclusion, sertindole, like haloperidol and clozapine, can reduce raised mesolimbic dopaminergic activity in the rat. Sertindole differs from haloperidol by its ability to return the hyperactivity response to control levels. © 1994 Wiley-Liss, Inc.     

A novel,orally effective hypoglycemic agent,SaRI 59–801, in laboratory animals

SaRl 59-801 (59-801) (α-[dimethylaminomethyl]-2-[3-ethyl-5-methyl-4-isoxazolyl]-1H-indole-3-methanol), is a novel, orally effective hypoglycemic compound which appears to act largely, if not entirely, by stimulation of insulin release. The compound is structurally unrelated to sulfonylurea derivatives. The 2-hr hypoglycemic ED₂₅ in fasting mice was 110 mg/kg; the plasma insulin levels were increased, with an ED₅₀ of 47 mg/kg. Significant hypoglycemic activity was observed 2 hr after oral administration of 59-801 to fasting rats (ED₂₅ = 86 mg/kg), while plasma insulin was elevated by 62% at 100 mg/kg. 59-801 caused an insignificant decrease in plasma lactic acid levels. The hyperglycemic response 30 min after an oral starch load was inhibited by 1-hr pretreatment with 59-801 (ED₅₀ = 37 mg/kg). No tolerance to the hypoglycemic effect was observed after 28 days of dosing in rats. In monkeys, the agent also produced hypoglycemia with a minimum effective dose of 10 mg/kg and an ED₂₅ of 33 mg/kg for a period of 6 hr after oral administration. In genetically diabetic (db⁺/db⁺) mice, 59-801 was more potent in producing hypoglycemia (ED₂₅ = 47 mg/kg) than their lean littermates (ED₂₅ = 131 mg/kg). In alloxan-diabetic rats or streptozotocin-diabetic mice, this agent was inactive at 200 mg/kg, but at 400 mg/kg, it caused reduction of blood glucose levels of 29–39 and 21%, respectively, possibly the result of stimulation of residual β-cell function. Thus far, stimulation of insulin release is the only mechanism found to explain the acute hypoglycemic activity of 59-801.     

Effects of acute and subacute cadmium administration on carbohydrate metabolism in mice

The administration of single doses of cadmium acetate (2.0–6.0 mg/kg, ip) produces hyperglycemia and glucose intolerance in intact mice. Adrenalectomy prevents the hyperglycemic effect but not the glucose intolerance. Glucose intolerance is associated with a decreased pancreatic secretory activity as evidenced by decreased insulinogenic indices in Cd-treated mice. The administration of 4.0 mg/kg of Cd daily for 14 days produces tolerance to Cd-induced hyperglycemia. The subacute treatment did not produce changes in resting blood glucose levels, nor did it produce a decrease in glucose tolerance. A significant reduction in circulating serum insulin was detected after subacute Cd administration. It is suspected that a Cd-induced decrease in renal threshold to glucose masks the effect of lowered serum insulin concentrations.     

Effect of inhibitors of drug metabolism on mitochondrial swelling and on carbon tetrachloride-induced lysosomal damage

Several inhibitors of drug metabolism were found to be very potent for causing mitochondrial swelling at concentrations in the range from 1 to 100 μm. Moreover, they are also effective in increasing lysosomal loss of enzymes at concentrations from 1 to 100 μm. The inhibitors of drug metabolism were not able to stabilize lysosomes against CCl₄-induced lysosomal damage at concentrations from 0.001 to 100 μm. 2-Diethylaminoethyl-2,2-diphenylvalerate hydrochloride (SKF 525A) administration to rats at a dose of 50 mg/kg ip increased the in vitro lysosomal lability to CCl₄ at 1 hr but not at longer periods of time after administration. Curiously some stabilizing effect was found 14 hr after SKF 525A administration if the injection was made at 8 pm instead of the usual time of 8 am. The administration of another inhibitor, ethyl N-(2-diethylaminoethyl) 2-phenyl-2-ethylmalonamate hydrobromide (Sch 5706) did not cause any effect on lysosomal stability.     

Acetaminophen decreases adenosine 3'-phosphate 5'-phosphosulfate and uridine diphosphoglucuronic acid in rat liver

The purpose of this investigation was to determine the effects of acute administration of acetaminophen on adenosine 3'-phosphate 5'-phosphosulfate (PAPS) and UDP-glucuronic acid concentrations in fed male rats. Acetaminophen produced a dosage-dependent decline in rat hepatic PAPS concentrations which was significant after dosages of 150, 300, or 600 mg/kg, ip. The time course of the decline in PAPS values after 600 mg acetaminophen/kg showed that PAPS concentrations reached a nadir 1 hr after dosing (40% of control values). Serum sulfate concentrations were also decreased by large dosages of acetaminophen (32 and 15% of control 2 hr after 150 and 600 mg/kg, respectively) and a significant, positive correlation between serum sulfate and hepatic PAPS concentrations was noted. In addition, hepatic cysteine and glutathione concentrations were lowered by high dosages of acetaminophen. Hepatic UDP-glucuronic acid concentrations were greatly decreased for 2 hr after a dosage of 600 mg acetaminophen/kg (15, 23, and 42% of control 0.5, 1.0, and 2.0 hr after dosing, respectively) whereas 150 mg/kg produced a less pronounced and more transient decrease. These findings demonstrate that both PAPS and UDP-glucuronic acid concentrations in liver are decreased after administration of acetaminophen and imply that capacity-limited sulfation and glucuronidation of acetaminophen are due to a decrease in co-substrate availability.