Biomedical subjects

A Yoshitake

Publications and source records attributed to A Yoshitake.

At least 55 records · Page 3Linked to original sources

PubMed1992

[Mammalian toxicity of empenthrin (Vaporthrin, S-2852F)].

1. Acute toxicity: Empenthrin ((RS)-(EZ)-1-ethynyl-2-methyl-2-pentenyl (1R)-cis/trans-chrysanthemate) caused some toxic signs such as muscular fibrillation, tremor, hypersensitivity, decrease of spontaneous activity, ataxic gait, lymb paralysis, irregular respiration, excretion of oily substance, loose stool and urinary incontinence in oral acute toxicity studies at 1000 mg/kg and above in rats, and at 2000 mg/kg and above in mice. The oral LD50 value was estimated greater than 5000 mg/kg (male) and greater than 3500 mg/kg (female) in rats and greater than 3500 mg/kg (both sexes) in mice. In both rats and mice, the toxic signs were not found at 2000 mg/kg by dermal administration. The dermal LD50 value was estimated greater than 2000 mg/kg (both sexes) in both rats and mice. The LC50 value in rats for the acute inhalation toxicity of empenthrin was estimated to be greater than 4610 mg/m3 for both sexes. The LC50 value in mice was determined to be 2700 mg/m3 for male and 2300 mg/m3 for female. Mice showed higher sensitivity to empenthrin than rats. 2. Reproductive and developmental toxicity: Empenthrin was orally administered to fetal organogenesis periods of rats at the dose levels of 50, 150 and 500 mg/kg, and of rabbits at 100, 300 and 1000mg/kg. Maternal toxicity was found at 500 mg/kg in rats and at 300 mg/kg or more in rabbits. There were no teratogenicity, no embryotoxicity and no fetal retardation in rats or rabbits. In addition, there were no adverse effects on F1 pups growth, development or reproductive performance. 3. Subchronic toxicity: Empenthrin was orally administered to male and female SD rats at dose levels of 0 (corn oil), 10, 100 and 300 mg/kg for 26 weeks. Clinical signs, body weight, food and water consumption were monitered, and hematological, blood biochemical, ophthalmological and histopathological examination were carried out. As a result, changes related to administration of empenthrin were observed mainly in the liver and kidneys in rats receiving 100 mg/kg or more. Therefore, the no-effect-level of empenthrin is determined to be 10 mg/kg in both sexes of rats in this study.

Administration, Oral↗

PubMed1991

Hepatic UDP-glucuronyltransferase(s) activity toward thyroid hormones in rats: induction and effects on serum thyroid hormone levels following treatment with various enzyme inducers.

Induction of hepatic UDP-glucuronyltransferase(s) (hUDP-GT(s] activity toward thyroid hormones and the relationship between the activity and the serum thyroid hormones or the thyroid stimulating hormone (TSH) level were examined in male Sprague-Dawley rats after four consecutive ip doses of various hepatic enzyme inducers at 75-150 mg/kg/day. hUDP-GT activity toward thyroxine (T4; hUDP-GT-T4) was induced by treatment with beta-naphthoflavone, 3-methylcholanthrene (3-MC), polychlorinated biphenyls, or pregnenolone-16 alpha-carbonitrile. However, no significant induction was observed for isosafrole administration and in the cases of phenobarbital and 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane slight decreases were found. The induction profile of hUDP-GT-T4 for these inducers was approximately the same as that of hUDP-GT activity toward triiodothyronine (T3; hUDP-GT-T3), indicating that these two thyroid hormones (T4 and T3) are glucuronidated by the same hUDP-GT(s). Moreover, the induction profile of both hUDP-GT-T4 and hUDP-GT-T3 was similar to that of hUDP-GT toward 1-naphthol, but not chloramphenicol, suggesting that T4 and T3 belong to the so-called group-1 substrates which are preferentially glucuronidated by hUDP-GT(s) inducible by treatment with 3-MC. Decreases in serum T4 levels clearly correlated with an increase in hUDP-GT-T4 activity, indicating that serum T4 levels are directly affected by hUDP-GT-T4 activity. However, no direct correlation between decrease in thyroid hormone levels and compensatory increase in TSH levels was found.

Animals↗

PubMed1991

Behavior of alpha 2u-globulin accumulating in kidneys of male rats treated with d-limonene: kidney-type alpha 2u-globulin in the urine as a marker of d-limonene nephropathy.

Effects of d-limonene on alpha 2u-globulin in the kidneys, urine and serum were examined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblotting analysis. Treatment of male rats with d-limonene by gavage for 14 consecutive days (300 mg/kg/day) caused accumulation of hyaline droplets in renal proximal tubule cells, and a marked intensification of a protein band corresponding to the kidney-type alpha 2u-globulin, with a molecular weight calculated to be approximately 16 kDa. However, no significant changes in the serum alpha 2u-globulin (native-type) band, of approximately 19 kDa, were observed between treated rats and controls, suggesting that circulating alpha 2u-globulin levels were not affected by the d-limonene administration. While the molecular weight of the major alpha 2u-globulin in the urine from control rats was the same as that in the serum (native-type), marked increase in the protein band corresponding to kidney-type-alpha 2u-globulin was observed in the urine from treated rats. The results were indicative of elimination of alpha 2u-globulin from the kidney to urine, the appearance of kidney-type-alpha 2u-globulin in urine implying disruption or exfoliation of proximal tubule cells. Therefore, it is suggested that the presence of the alpha 2u-globulin (kidney-type) in the urine might be used as an indicator of chemically induced alpha 2u-globulin nephropathy.

Alpha-Globulins↗

PubMed1991

Age-related changes in metabolism of diethofencarb: relationship between metabolism in rat and hepatic drug-metabolizing enzyme activities.

1. Age-related changes in metabolism of diethofencarb (DFC) (isopropyl-1,4-diethoxycarbanilate) and hepatic drug-metabolizing enzyme activities were studied in male Sprague-Dawley rats aged 2, 8, 16 and 21 months. 2. Following a single oral dose of 14C-DFC (500 mg/kg), the major route of elimination of the 14C for 7 days was urine (85.6-97.8%) at all ages. 3. Analysis of urinary metabolites showed that deethylation of 14C-DFC was constant for all age groups; however, sulphation and acetylation significantly decreased, and glucuronidation increased, with age. 4. Hepatic PAPS-sulphotransferase and acetyl-CoA: N-acetyltransferase in DFC metabolism significantly decreased with age, whereas no significant effects of ageing on O-deethylase and UDP-glucuronyltransferase were observed. 5. Results show that age-related differences in the ratios of urinary metabolites of DFC resulted to some extent from changes in the hepatic drug-metabolizing enzyme activities.

Aging↗

PubMed1989

Efficient high-performance liquid chromatographic system for protein purification.

An efficient high-performance liquid chromatographic system, consisting of an affinity column and a high-performance size-exclusion column, was developed and applied to the purification of growth hormone receptors from rabbit livers. When a 6-ml sample of Triton X-100 extracts containing 16 mg of protein was applied to the system, 1200-fold purified receptor with a 10% recovery of binding activity from homogenates was obtained within 3-4 h. The purified receptor exhibited one main band on sodium dodecyl sulphate polyacrylamide gel electrophoresis, and the affinity constant (Ka = 6.0.10(9) M-1) was found to be comparable with that of 1% Triton X-100 extract (4.4.10(9) M-1). The injection of 1 ml of 3 M urea solution prior to receptor elution with 10 ml of 6 M urea solution was effective in removing non-specific binding proteins.

Animals↗

PubMed1989

Mutagenicity studies on fenitrothion in bacteria and mammalian cells.

The mutagenicity of fenitrothion was determined in strains of Salmonella typhimurium and Escherichia coli. Fenitrothion was found to be non-mutagenic in Salmonella typhimurium strains of TA98, TA1535 and TA1537 and in Escherichia coli WP2uvrA both with and without S9 mix, while weak mutagenicity was observed only in Salmonella typhimurium TA100 and enhanced by the addition of S9 mix. The mutagenicity observed in the TA100 strain was not expressed in a nitroreductase-deficient strain, TA100 NR, and decreased in a transacetylase-deficient strain, TA100 1,8-DNP6. The mutagenicity of fenitrothion was also examined by a gene mutation assay using the gene for hypoxanthine-guanine phosphoribosyltransferase (hgprt) in V79 Chinese hamster lung cells. Fenitrothion did not induce any increment of 6-thioguanine-resistant mutant cells at doses ranging from 0.01 to 0.3 mM regardless of the presence or absence of S9 mix. These results suggest that reduction of fenitrothion by a bacterial nitroreductase of TA100 to an active form is essential for the expression of the mutagenicity of fenitrothion in TA100 and that a bacterial transacetylase of TA100 also has an important role in the process of mutagenic activation.

Animals↗

PubMed1989

DNA-adduct formation in the forestomach of rats treated with 3-tert-butyl-4-hydroxyanisole and its metabolites as assessed by an enzymatic 32P-postlabeling method.

Formation of DNA-adducts by 3-BHA or its metabolites, i.e., tert-butyl-1,4-benzoquinone (TBQ) and 5-methoxy-3-tert-butyl-1,2-benzoquinone (3-TBOQ), as well as DNA-adduct formation by 4-nitroquinoline-N-oxide (4NQO), in rat forestomach were examined by an enzymatic 32P-postlabeling assay. Four DNA-adducts were clearly detected in the forestomach after treatment of rats with 4NQO. The sensitivity was 1.9 certain adducts per 10(8) normal nucleotides. On the contrary, no DNA adducts were detected in the forestomach of rats given either a single or repeated oral administration (5 days) of 3-BHA, TBQ or 3-TBOQ. The analyses were carried out under conditions which could detect the DNA-adducts produced by reaction of TBQ with calf thymus DNA in vitro. The results suggest that formation of aromatic adducts in vivo by 3-BHA, TBQ or 3-TBOQ in the rat forestomach-DNA is not evident or at least below the detection limits of the current bioassay.

4-Nitroquinoline-1-oxide↗

PubMed1988

Metabolism of 2- and 3-tert-butyl-4-hydroxyanisole in the rat (III): Metabolites in the urine and feces.

The urinary and fecal metabolites of orally administered 2-tert-butyl-4-hydroxyanisole (2-BHA) and 3-tert-butyl-4-hydroxyanisole (3-BHA) in rats were identified. Samples of 2-day pooled urine and feces of rats given a single intragastric dose of 1 g/kg body wt of tert[butyl-14C]3-BHA (*Bu-3-BHA). tert[butyl-14C]2-BHA (*Bu-2-BHA), [methyl-14C]3-BHA (*Me-3-BHA) or [methyl-14C]-2-BHA (*Me-2-BHA) were analyzed by comparing thin-layer chromatography (TLC) retentions with authentic standards. Conjugated metabolites were identified after enzymatic hydrolysis. Proton magnetic resonance spectroscopy and electron impact mass spectrometry were used for confirmation of the authentic standards. In rats given 3-BHA, a major metabolite in the urine was 3-BHA-glucuronide with a smaller amount of tert-butylhydroquinone (TBHQ)-sulfate, while unchanged 3-BHA and 3-BHA-glucuronide were detected in the feces. In rats given 2-BHA, the main metabolites were the sulfate conjugates of 2-BHA, 4-tert-butyl-5-methoxy-1,2-benzoquinone (2-TBOQ) and the glucuronide of 2-BHA in the urine, while unchanged 2-BHA was found in the feces.

Administration, Oral↗

PubMed1988

Substrate specificity for formation of cholesterol ester conjugates from fenvalerate analogues and for granuloma formation.

1. The substrate specificity of microsomal carboxyesterase(s) responsible for the formation of cholesteryl [2R]-2-(4-chlorophenyl) isovalerate from fenvalerate was investigated by incubating mouse kidney microsomes with 14C-cholesterol and the following substrates: fenvalerate isomers, fenvalerate analogues, other pyrethroids, methoprene and cycloprate analogues. Among the four isomers of fenvalerate, only the [2R, alpha S]-isomer yielded a cholesterol ester, being identical with the result obtained in the in vivo study. Some fenvalerate analogues produced cholesterol ester conjugates, but no other pyrethroids nor methoprene produced such conjugates. Some cycloprate analogues gave the corresponding cholesterol ester, the yields of which were dependent on their carbon-chain lengths. 2. Cholesterol ester formation in vitro from these fenvalerate analogues was well correlated with granuloma formation observed when the analogues were given to mice at 3000 ppm for a month. 3. Steroids other than cholesterol were also investigated as acceptors of the acid moiety of the [2R, alpha S]-isomer by incubating solubilized carboxyesterase(s) with the [2R, alpha S]-isomer in the presence of egg lecithin and several steroids. Dehydroisoandrosterone and pregnenolone were found to give the corresponding ester conjugates.

Animals↗

PubMed1987

In vitro evaluation of radioiodinated butyrophenones as radiotracer for dopamine receptor study.

Radioiodinated butyrophenone compounds are attracting the interest of those working on dopamine receptor studies; structure-activity relationship study has revealed the ortho position of the p-fluorobutyrophenone moiety as a very plausible iodination site. Various synthesized butyrophenones iodinated at the ortho position of p-fluorobutyrophenone moiety, 2'-iodohaloperidol (2'-IHP), 2'-iodotrifluperidol (2'-ITP) and 2'-iodospiperone (2'-ISP) were tested for their abilities to inhibit 3H-spiperone (SP) binding for the dopamine (D-2) receptor, together with reference compounds (SP, haloperidol(HP) and 4-iodospiperone (4-ISP]. The order of binding affinity of the tested compounds was SP greater than 2'-ISP greater than HP greater than 4-ISP greater than 2'-IHP greater than 2'-ITP. Whereas, the serotonin (S-2) receptor binding affinity of SP and its iodinated analogues were in the order of SP much greater than 4-ISP greater than 2'-ISP. Furthermore, in the saturation binding study using the striatal membrane preparations, the 2'-ISP displayed a KD of 0.25 nM with maximum number of binding site Bmax of 210 fmol/mg protein. These data indicated the 2'-ISP as holding high affinity for dopamine receptors and a low affinity for serotonin receptors. Thus, the 125I-2'-ISP was a very potent radioligand for in vitro dopamine (D-2) receptor studies, and 123I-2'-ISP holds very promising characteristics as for in vivo dopamine receptor studies, as well.

Animals↗

PubMed1987

Radioiodinated 2'-iodospiperone: a new radioligand for in vivo dopamine receptor study.

In vivo dopamine receptor binding of the newly synthesized ligand, 125I-2'-iodospiperone (125I-2'-ISP), was studied in mouse brain. The highest accumulation was found in the striatum. Analysis of the striatal homogenate showed the 125I-2'-ISP to be metabolically stable. Furthermore, this striatal binding was saturable and displaced only by dopaminergic drugs. On the other hand, the accumulation in the cortex was as low as that of the cerebellum and uneffected by the administration of serotoninergic drugs and dopaminergic drugs; results assessed by macroautoradiographic studies. Thus, the newly synthesized 125I-2'-ISP presented high affinity for dopamine receptors in vivo and therefore, holds great potential for the in vivo dopamine receptor studies, provided 123I becomes readily available.

Animals↗

PubMed1987

High-performance liquid chromatographic system for the rapid purification of growth-hormone receptor in rabbit livers.

A system consisting of high-performance affinity chromatography and size-exclusion chromatography has been developed for the rapid purification and isolation of relatively labile membrane proteins, such as growth-hormone receptor. The crude membrane sample containing growth-hormone receptor was obtained from rabbit livers by ultracentrifugation, followed by solubilization with Triton X-100. The sample was introduced into the high-performance affinity gel column through a large-volume loop injector. After removal of unretained proteins, the fraction containing the growth-hormone receptor was eluted with 6 M urea solution. The eluate from the affinity column passed directly into the size-exclusion gel column, where rapid desalting and separation from contaminants were achieved. The eluate was monitored by UV absorption at 280 nm and fractionated for the subsequent binding assay with 125I-labelled human growth hormone.

Animals↗

PubMed1987

Metabolism of 2- and 3-tert-butyl-4-hydroxyanisole (2- and 3-BHA) in the rat (I): Excretion of BHA in urine, feces and expired air and distribution of BHA in the main organs.

The mechanism of the carcinogenic or toxic action of BHA on rat forestomach was examined by studies on the excretion and tissue distribution of radioactivity in F344 male rats given tert-butyl- or methoxy-labelled 3-BHA orally. Within 2 days after a single oral dose of labelled BHA at 1 g/kg body wt, 87-96% of the 14C was excreted, mainly in the urine with smaller amounts in the feces and expired air. More 14C was found in the tissues of rats given the methoxy-labelled compounds. The distributions of 14C in the forestomach and the glandular stomach were similar. At 168 h after treatment, more 14C was found in the forestomach of rats given 2-BHA than in that of rats given 3-BHA. These results indicate that excretion of BHA is rapid, that 4-O-methyl demethylation may take place readily and that demethylated methyl group may become distributed non-specifically in tissues. The carcinogenic or toxic action of BHA on the forestomach does not seem to be due accumulation of BHA in the forestomach.

Air↗

PubMed1987

Metabolism of 2- and 3-tert-butyl-4-hydroxyanisole (2- and 3-BHA) in the rat. (II): Metabolism in forestomach and covalent binding to tissue macromolecules.

The mechanism of action of 2(3)-tert-butyl-4-hydroxyanisole (2-BHA or 3-BHA) on rat forestomach epithelium was studied by examining the metabolites of BHA in the stomach and the covalent binding of BHA to macromolecules in the forestomach epithelium. Male F344 rats 6 weeks old were given a single intragastric injection of 1 g/kg body wt of [tert-14C]-3-BHA (Bu-3-BHA) or [methyl-14C]-3-BHA (Me-3-BHA), and 6 h later BHA metabolites in the forestomach, glandular stomach and stomach contents were examined by thin-layer chromatography. No significant amounts of metabolites were detected in the forestomach or glandular stomach epithelium and almost all the radioactivity in these tissues was extracted with organic solvents. In in vitro experiments also, no significant amounts of metabolites were detected when the 9000 g supernatant of the forestomach or glandular stomach epithelium, or gastric juice was incubated with Bu-3-BHA in the absence or presence of NADPH. In binding studies, rats were given Bu-3-BHA, [tert-14C]-2-BHA (Bu-2-BHA), Me-3-BHA or [methyl-14C] butylated hydroxytoluene (Me-BHT) intragastrically at a dose of 1 g/kg body wt with or without pretreatment with unlabelled 1% 3-BHA or BHT in the diet for 6 days. Six hours after treatment with a labelled compound, the rats were sacrificed and the DNA, RNA and protein of their forestomach, glandular stomach, liver and kidney were isolated. Bu-3-BHA, Bu-2-BHA and Me-3-BHA did not bind covalently to forestomach DNA or RNA, and the amounts of radioactivity of these compounds bound to proteins in the 4 tissues were similar. These findings suggest that BHA acts on the forestomach epithelium directly without metabolic activation, and that its action is not related to its binding to DNA or RNA.

Animals↗

PubMed1987

[One-year chronic dietary toxicity study of d.d-T80-prallethrin in rats].

d.d-T80-prallethrin, a pyrethroid insecticide for sanitary use, was administered to Crj : CD (Sprague Dawley) rats at concentrations of 120, 600 or 3,000 ppm in diet for one year to assess the chronic toxicity potential and the reversibility. The summarized results obtained are as follows: 1. Chronic toxicity study 3,000 ppm : Decreases in body weight gain, food consumption, and water intake were observed. Slight alopecia in the neck and/or back was noticed during the first and second weeks, but the animals were recovered thereafter. Slight anemic changes such as decreases in hemoglobin concentration, hematocrit value, MCV and MCH were observed in the females at 52 week. Blood biochemistry revealed increases in total cholesterol (in the males and females at 13, 26 and 52 weeks), phospholipid (in the males and females at 13, 26 and 52 weeks), albumin (in the males at 13 and 26 weeks, in the females at 52 week), total protein (in the males at 26 week, in the females at 52 week), A/G ratio (in the males at 13 week, in the females at 26 week), creatinine (in the males at 52 week), urea nitrogen (in the females at 52 week), GOT (in the males and females at 52 week) and GPT (in the males and females at 52 week), and decreases in triglyceride (in the females at 26 and 52 weeks) and alkaline phosphatase (in the males at 13 and 52 weeks). In urinalysis, an increase in bilirubin was observed in the males at 52 week. Gross-pathology revealed a lower incidence of accentuated lobular pattern of liver (in the males at 26 week) and a higher incidence of enlarged liver (in the males at 52 week). In organ weight, increases in liver (in the males and females at 26 and 52 weeks), kidney (in the males at 26 and 52 weeks) and thyroid weights (in the males at 26 and 52 weeks, in the females at 26 week), and decreases in spleen (in the females at 26 and 52 weeks) and adrenal weights (in the females at 52 week) were observed. Histopathological examination revealed a lower incidence of fatty metamorphosis in the liver of females at 52 week. 600 ppm: An increase in liver weight was observed in the males at 26 week. 120 ppm: No effect was observed. 2. Reversibility study Almost all the above chronic toxicities were reversible.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1985

Benzodiazepines and their metabolites: relationship between binding affinity to the benzodiazepine receptor and pharmacological activity.

Experiments were carried out to study the relationship between binding affinity to the benzodiazepine receptor and pharmacological activity, especially anti-anxiety activity, of clinically useful benzodiazepines. In the in vitro experiments, fludiazepam showed the highest affinity to the benzodiazepine receptor with 4 times more potency than that of diazepam, which paralleled the in vivo activity. Diazepam and nimetazepam also bound with high affinities as expected from their in vivo activities. On the contrary, medazepam and cloxazolam showed extremely low affinities and oxazolam showed no affinity, although they showed moderate in vivo activity. However, their metabolites were found to have both high affinity and in vivo activities. These results strongly suggest that in the case of medazepam, cloxazolam and oxazolam, their metabolites may bind to receptor sites in the brain and then elicit pharmacological action. This conclusion was supported by the fact that a good correlation between the binding affinity and the anti-anxiety activity of the tested compounds was observed.

Animals↗

PubMed1985

Radioimmunoassay of bencyclane in human serum.

A radioimmunoassay of bencyclane in human serum was developed. Male rabbits were immunized with p-(3-carboxy-propoxy)bencyclane-bovine serum albumin conjugate, giving antisera with high titers. 125I-p-Hydroxybencyclane with a high specific activity was prepared as a labelled antigen by a chloramine-T method. In the radioimmunoassay procedure, a mixture of serum sample, diluted antiserum and 125I-antigen solution were incubated at 4 degrees C for 18 h, and bound-free separation was carried out by a dextran-coated charcoal method. The detection limit of bencyclane in human serum was 1.0 ng/ml, and the cross-reactivity of the antiserum with metabolites was found to be very low. Serum samples from healthy volunteers dosed orally with bencyclane fumarate were analyzed by both of the radioimmunoassay and gas chromatography-mass spectrometric methods. An excellent correlation was observed between the values obtained by both methods.

Animals↗

PubMed1985

A method for measuring specific activities of 14C-labelled compounds by gas chromatography-mass spectrometry-computer system.

A method for measuring specific activities of 14C-labelled compounds by gas chromatography-mass spectrometry-computer system (GC-MS-CPU) was developed. This method was proved to provide practically precise and accurate specific activities of various 14C-labelled compounds with such merits as requirement of small amount of samples, being applicable to volatile compounds, and convenience. The C.V. percent obtained for tested compounds was within 3.9 and the reliable sensitivity should be over 37 MBq/mM (1 mCi/mM). This method was also useful for obtaining information on the labelling pattern and the synthetic procedures applied.

Carbon Radioisotopes↗