[The mechanism of dural permeability to narcotics and local anesthetics].
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Anesthetics, Local↗
Biomedical subjects
K Hiraga
Publications and source records attributed to K Hiraga.
Irreversible in vivo binding of thiabendazole to macromolecules in pregnant mice and its relation to teratogenicity.
The binding of [14C]thiabendazole ([14C]TBZ) to macromolecules in the liver, foetus and other tissues was investigated in Jcl:ICR mice on day 13 of gestation. TBZ suspended in olive oil was given orally in a dose of 1 g/kg body weight (5 microCi/mouse) and the mice (in groups of three) were killed 0.5, 1, 3, 6, 24 and 96 hr later. The bound radioactivity in the liver and foetus was at a maximum between 3 and 24 hr after treatment. The rate of decrease of the bound radioactivity was slower than that of total radioactivity. Bound radioactivity was also present in other tissues (including kidney, lung, heart, placenta and spleen). The level of bound radioactivity was measured in the liver and foetuses after oral administration of teratogenic doses of 200-1600 mg/kg. Disproportionate increases in bound radioactivity were observed in both tissues after administration of the highest dose.
Abnormalities, Drug-Induced↗
Lung hemorrhagic toxicity of butylated hydroxyanisole in the rat.
Male Sprague-Dawley rats were injected intraperitoneally (i.p.) with butylated hydroxyanisole (BHA) at doses of 0, 1, 4, 16, 64, 256, 384, 576, 864, 1296 and 1944 mg/kg/day for 7 days. Deaths occurred in a dose- and time-dependent manner when BHA was given in amounts greater than 576 mg/kg. The LD50 was 881 (484-1440) mg/kg. Intracranial hemorrhage was found in the dead rats, and lung hemorrhage was observed in the survivors given BHA at doses greater than 384 mg/kg/day. Histopathologically, intra-alveolar hemorrhages, thickening of alveoli and deposition of lipids in the lungs were observed. The prothrombin index was decreased only in rats given BHA at a level of 384 mg/kg/day. These observations suggest that BHA and/or its metabolite cause pulmonary hemorrhagic damage in rats. The mechanism of hemorrhage may be different from that of bleeding induced by butylated hydroxytoluene.
Animals↗
Effect of cobaltous chloride on butylated hydroxytoluene-induced hepatic necrosis in rats.
Although a single dose of butylated hydroxytoluene (BHT); 1000 mg/kg to rats induced a hepatic injury accompanying centrilobular necrosis, the pretreatment with cobaltous chloride, an inhibitor of cytochrome P-450 synthesis, could inhibit the damage. The marked elevations of serum transaminase activities and bile acid content induced by BHT were diminished to nearly the control level by pretreatment with cobaltous chloride. The protective effect of cobaltous chloride on BHT-induced hepatotoxicity is discussed.
Animals↗
Differences in the haemorrhagic toxicity of aspirin between rats and mice.
Rats and mice were fed a diet containing aspirin at levels of 0, 0.3, 0.6 and 1.2% for 1 and 4 weeks. Haemorrhagic death and/or haemorrhagic anaemia occurred in rats in a dose-dependent manner. Prothrombin and kaolin-activated partial thromboplastin time indices were also decreased depending on the daily doses. However, no conspicuous haemorrhagic signs were found in mice given aspirin. These results suggest marked differences in haemorrhagic effects of aspirin between rats and mice. From results of supplementary experiments with two metabolites of aspirin, salicylic acid and gentisic acid, and from the fact of close relationship between hepatic concentration of salicylic acid and haemorrhagic effects of aspirin, it is inferred that salicylic acid may be a precursor for the active metabolite(s) to cause haemorrhage. The mechanism of species differences of aspirin is discussed.
Animals↗
[The mechanism of action of E.coli endotoxin on oxidative phosphorylation of the rat liver mitochondria].
The effects of E.coli endotoxin on oxidative phosphorylation were investigated in vitro using isolated rat liver mitochondria. The respiratory control index (RCI) was significantly decreased by preincubation of mitochondria for 20 min. at 30 degrees C in the presence of the endotoxin, which repressed dose-dependently the state 3 respiration. The extent of the repression of this state 3 respiration was comparable with that of the exchange reaction of adenine nucleotide. The endotoxin, however, did not inhibit several mitochondrial enzymes including the electron transport system at the enzyme level. The exchange reaction and the number of the ADP-binding sites of the adenine nucleotide carrier were assayed using [14C] ADP and [3H] carboxyatractyloside, respectively. The exchange reaction was repressed by 72% and the number of binding site of carboxyatractyloside was decreased by 20% by the endotoxin (100 micrograms/mg mitochondrial protein). These effects of endotoxin on the adenine nucleotide carrier were additionally enhanced by the Ca2+ ion. The occurrence of these effects was prevented by EGTA or dibucaine, a potent inhibitor of phospholipase A2. These results suggested that the endotoxin may activate phospholipase A2 which may harm the lipid layer of the mitochondrial membrane.
Animals↗
Carcinogenicity testing of acetaminophen in F344 rats.
A study of acetaminophen (AAP) for possible carcinogenicity was conducted by administering the test chemical in pelleted diets to F344/DuCrj rats of each sex. Groups of 50 rats were administered AAP at one of two doses, either 0.45 or 0.9% for males and 0.65 or 1.3% for females. The rats were treated for 104 weeks, and then observed for 26 weeks. Control groups of 50 rats were fed basal diet throughout the study. Mean intakes of AAP by low- and high-dose rats were 195.4 and 402.1 in the males, and 335.7 and 688.0 mg/kg/day in the females, respectively. The survival rates at week 104 of each group were 86 to 90% in the males and 80 to 82% in the females. No pathologic or statistical evidence of induction of tumors by AAP was found. It is concluded that, under the conditions of this study, acetaminophen is not carcinogenic to F344/DuCrj rats of either sex.
Acetaminophen↗
Comparison of populations of mRNA coding fumarase in rat brain and liver.
The populations of mRNA encoding mitochondrial and cytosolic fumarases in the poly A+ RNA fractions purified from polysomes of rat brain and liver were examined. When the in vitro translation products programmed by the poly A+ RNA fraction obtained from rat brain were purified by immunoprecipitation with anti-fumarase antibody and analyzed by SDS polyacrylamide gel electrophoresis and fluorography, only one polypeptide of 50 KD was detected as a precursor of fumarase. In contrast, by the same method, two polypeptides of 50 KD and 45 KD, which is the same size as mature fumarase, were detected as precursors of rat liver fumarase. These results suggest that rat brain polysomes contain only one population of mRNA coding a 50 KD precursor of mitochondrial fumarase with little or no mRNA of the cytosolic fumarase, whereas rat liver polysomes contain two types of mRNA for mitochondrial and cytosolic fumarases, respectively. These findings are consistent with the fact that the brain is the only organ in rats known not to contain cytosolic fumarase.
Animals↗
[Changes in acid-base balance in arterial blood and cerebrospinal fluid (CSF) during hypothermia anesthesia].
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Acid-Base Equilibrium↗
On the mechanism of butylated hydroxytoluene-induced hepatic toxicity in rats.
The relations between serum transaminase activity and the hepatic contents of glutathione and lipid peroxide were examined following oral administration to rats of butylated hydroxytoluene (BHT; 500 or 1000 mg/kg). The glutathione level rapidly diminished and reached a minimum at 6 hr after BHT administration. The period of depletion was dependent on dose: restoration of the glutathione level took longer in high-dose rats than in low-dose rats. The content of hepatic lipid peroxide was not markedly changed by BHT throughout the experimental period. The activity of glutathione S-transferase was not affected until 12 hr after BHT administration but, thereafter, it increased with time and was accompanied by elevation of the glutathione level. Though the activities of serum glutamate-oxaloacetate transaminase and glutamate-pyruvate transaminase were not affected by low-dose BHT, they increased rapidly in the high-dose rates after a lag period of about 6 hr and reached a maximum at 24 hr after administration; at that time, the livers of the high-dose rats showed centrilobular necrosis. The results indicate that acute hepatic injury was induced by the high-dose BHT. Pretreatment with cobaltous chloride inhibited the increase in the activities of the serum transaminases produced by the high-dose of BHT accompanying the depletion of microsomal cytochrome P-450 content and the induction of glutathione content. These observations suggest that hepatic damage was associated with prolonged depletion of glutathione rather than with lipid peroxidation in the liver, and that the activated metabolites of BHT rather than the parent compound induced the tissue damage.
Alanine Transaminase↗
Preventive effect of cysteine on butylated hydroxytoluene-induced pulmonary toxicity in mice.
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Animals↗
Induction of chromosome aberrations and sister-chromatid exchanges in CHO-K1 cells by o-phenylphenol.
o-Phenylphenol (OPP), is used in Japan as a fungicide in food additives for citrus fruits. The induction of chromosome aberrations and sister-chromatid exchanges (SCEs) by OPP in cultured Chinese hamster ovary (CHO-K1) cells was studied. Cells were exposed to various concentrations of OPP ranging from 50 to 175 micrograms/ml for 3 h, and further incubated for 27 and 42 h. These incubation periods are almost equal to 2 and 3 cell cycles. SCEs and chromosome aberrations were induced by OPP at concentrations of 100, 125 and 150 micrograms/ml after the incubation for 27 h. For chromosome aberrations, chromatid breaks and exchanges there was a dose-dependent increase. Diplochromosomes due to endoreduplication were also caused by the same concentrations of OPP in a dose-dependent manner. After incubation for 42 h, chromosome aberrations were also increased by OPP at concentrations of 100 and 125 micrograms/ml, but the frequencies of SCEs were not significantly different from those of the control. These results suggest that OPP has a cytogenetic toxicity, and that the DNA damage resulting in SCEs induced by OPP is relatively short-lived and can be repaired during the longer incubation time.
Animals↗
Effects of dietary butylated hydroxytoluene on functional and biochemical properties of platelets and plasma preceding the occurrence of haemorrhage in rats.
Measurements of platelet-particle concentration, platelet haematocrit and mean platelet volume showed no significant differences between control rats and rats given 1.2% butylated hydroxytoluene (BHT) in the diet for 1 wk, but the platelet distribution width was significantly smaller in the rats fed BHT. By optical measurement, epinephrine-induced platelet aggregation was found to be significantly decreased in both the platelet-rich plasma and washed platelets of rats given BHT. Phosphatidylethanolamine in the platelet lipid was significantly increased by BHT treatment, while in the total lipid of the platelets, linoleic acid and eicosatrienoic acid were increased and arachidonic acid was decreased. The arachidonic/linoleic ratio was decreased by about 50% in the platelets of BHT-treated rats. BHT ingestion also changed the lipid composition, the concentration of lipid hydroperoxides and the zinc content of the plasma. The relationship of the observed effects to haemostatic function is discussed.
Animals↗
Induction of tumours of the urinary bladder in F344 rats by dietary administration of o-phenylphenol.
o-Phenylphenol (OPP), a fungicide approved as a food additive in Japan, was given in pelleted diets at dietary levels of 0.156, 0.313, 0.625, 1.25 or 2.5% to groups of 11 or 12 F344/DuCrj rats of each sex for 13 wk, and 0.625, 1.25 or 2.5% to groups of 20-24 male F344/DuCrj rats for 91 wk. In the 13-wk study, transitional cell papillomas of the urinary bladder occurred in 6/12 (50%) of the male 1.25% group. In the 91-wk study, urinary bladder tumours appeared in 23/24 (96%) of the 1.25% and 4/23 (17%) of the 2.5% group. Among these tumours, transitional cell carcinomas were found in 20/23 (87%) of 1.25% and 2/4 (50%) of the 2.5% groups. A dose-related increase in the incidence of nephritic lesions was also observed in dosed rats in both the 13- and 91-wk study.
Administration, Oral↗
The maternal-foetal distribution of thiabendazole administered in two different vehicles to pregnant mice.
We have compared the effects of two vehicles on the maternal-foetal distribution of 14C-thiabendazole ([14C]TBZ) given orally to Jcl: ICR mice on day 9 or 16 of gestation. TBZ, either suspended in olive oil (TBZ-O) or in a 0.5% aqueous solution of gum arabic (TBZ-G), was given orally on day 9 of gestation at a dose of 1 g/kg body weight (1 microCi/mouse). The mice were killed 0.5, 1, 3, 6, 12, 24 or 72 hr later. In mice treated with TBZ-O maximum levels of radioactivity in plasma and conceptuses were observed at 0.5 hr, whereas in those treated with TBZ-G maximum 14C levels were observed at 6 hr. The uptake of radioactivity from TBZ-O into the plasma and conceptuses was significantly higher than that from TBZ-G. Only trace levels of radioactivity were detected at 72 hr in both treatment groups. The placental transfer of [14C]TBZ was examined in mice treated with doses of 1 g/kg body weight (1 microCi/mouse) given as TBZ-O or TBZ-G on day 16 of gestation. The radioactivity in foetuses, placentas and maternal plasma was higher in mice treated with TBZ-O than those given TBZ-G. The placental transfer of [14C]TBZ was also examined by whole-body autoradiography in mice treated on day 16 of gestation.
Animals↗
Teratogenicity of thiabendazole in ICR mice.
Thiabendazole (TBZ) was tested for teratogenicity using Jcl:ICR mice. TBZ suspended in olive oil was given orally to pregnant mice at different stages of organogenesis. All foetuses were removed from the uterus on day 18 of gestation, and were examined for external and skeletal anomalies. In mice given 700, 1300 or 2400 mg TBZ/kg body weight/day on days 7-15 of gestation, dose-dependent external and skeletal anomalies, especially cleft palate and fusion of vertebrae, were observed. In mice given a single dose of TBZ (2400 mg/kg) on any one of days 6-13, an increased number of malformations was observed. Various types of malformation occurred, especially in the mice treated on day 9. Reduction deformity of limbs was found in mice given TBZ on days 9-12, a change that has not previously been observed to occur spontaneously in normal ICR mice in our laboratory. In order to determine a dose-response relationship, groups of mice were given one of 17 doses of TBZ (30-2400 mg/kg) on day 9 of gestation. The number of litters having foetuses with reduction deformity of limbs and of those having foetuses with skeletal fusion increased in proportion to the dose of TBZ. The regression lines of Y (probit response) on X (log dose) for reduction deformity of limbs and for skeletal fusion were Y = 2.47X - 3.65 and Y = 1.54X + 0.48, respectively. The effective doses (ED1) for the two malformations were 362.0 and 26.4 mg/kg, respectively.
Animals↗
Intracellular distribution of fumarase in various animals.
The subcellular distribution of fumarase was investigated in the liver of various animals and in several tissues of the rat. In the rat liver, fumarase was predominantly located in the cytosolic and mitochondrial fractions, but not in the peroxisomal fraction. The amount of fumarase associated with the microsomes was less than 5% of the total enzyme activity. The investigation of the intracellular distribution of hepatic fumarase of the rat, mouse, rabbit, dog, chicken, snake, frog, and carp revealed that the amount of the enzyme located in the cytosol was comparable to that in the mitochondria of all these animals. The subcellular distribution of the enzyme in the kidney, brain, heart, and skeletal muscle of rat, and in hepatoma cells (AH-109A) was also investigated. Among these tissues, the brain was the only exception, having no fumarase activity in the cytosolic fraction, and the other tissues showed a bimodal distribution of fumarase in the cytosol and the mitochondria. The mitochondrial fumarase was predominantly located in the matrix. About 10% of the total fumarase was found in the outer and inner membrane, although it was unclear whether this fumarase was originally located in these fractions. No fumarase activity was detected in the intermembranous space.
Animals↗
Radioimmunoassay for serum levels of an anti-androgen TSAA-291 (Oxendolone) in rats.
A simple radioimmunoassay method was established to determine serum levels of a steroidal anti-androgen, TSAA-291 (Oxendolone, 16 beta-ethyl-17 beta-hydroxy-4-estren-3-one) utilizing ether-extract of serum. Using an antiserum raised against TSAA-291-3-oxime-BSA conjugate in a rabbit, a standard curve was obtained in the assay range from 30 pg to 12 ng/tube. Intra- and inter-assay coefficients of variation were calculated to be 11 and 21%, respectively. Recovery rate of unlabeled TSAA-291 was 84%. Cross-reaction with endogenous steroids was less than 0.2%. TSAA-291 estimates were compared with those determined after further purification on a Celite column, or with those assayed with a gas-liquid chromatograph. The difference between these estimates was less than 16 and 25%, respectively, suggesting little contribution of the metabolites of TSAA-291 to the estimates by the radioimmunoassay. After successive treatments of male rats with TSAA-291 in an aqueous suspension in daily doses of 5, 15 and 50 mg/kg body weight for two weeks, serum TSAA-291 levels were determined by the radio immunoassay and calculated to be 22.7, 76.9 and 194.9 ng/ml, respectively.
Animals↗