Biomedical subjects

H Yoshimura

Publications and source records attributed to H Yoshimura.

At least 307 records · Page 17Linked to original sources

PubMed1991

Metabolism in vitro of 3,4,3',4'- and 2,5,2',5'-tetrachlorobiphenyl by rat liver microsomes and highly purified cytochrome P-450.

Metabolism of two polychlorinated biphenyls, 3,4,3',4'- and 2,5,2',5'-tetrachlorobiphenyl (TCB), was studied using rat liver microsomes and the four forms of cytochrome P-450 (P-450), P-450b, P-450e, P-450c and P-450d. At first, effects of various inducers of P-450 such as phenobarbital (PB), 3-methylcholanthrene (MC), isosafrole (ISF) and pregnenolone 16 alpha-carbonitrile on the formation of metabolites of these TCBs by liver microsomes were compared. 3,4,3',4'-TCB was significantly metabolized by liver microsomes from MC-treated rats to form two previously reported metabolites, 4-hydroxy-3,5,3',4'-TCB and 5-hydroxy-3,4,3',4'-TCB with a relative ratio of 2.5:1. Incubation with microsomes from untreated or PB-treated rats produced none of the metabolites. On the other hand, 2,5,2',5'-TCB was metabolized to 3-hydroxy-2,5,2',5'-TCB most easily by liver microsomes from PB-treated rats and at a moderate rate by liver microsomes from ISF-treated rats. Activities of microsomes from untreated or MC-treated rats to hydroxylate 2,5,2',5'-TCB were low or undetectable. When these TCB hydroxylase activities were examined with a reconstituted system consisting of each P-450, reduced nicotinamide adenine dinucleotide phosphate (NADPH)-cytochrome P-450 reductase, dilauroylphosphatidylcholine and NADPH-generating system, only P-450c catalyzed both the 4- and 5-hydroxylations of 3,4,3',4'-TCB at a ratio of 2.2:1. On the contrary, the hydroxylation of 2,5,2',5'-TCB proceeded efficiently with P-450b and P-450e, being more efficient with the former. P-450d did not show any catalytic activity toward 3,4,3',4'-TCB and 2,5,2',5'-TCB.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Inhibitory effect of cannabidiol hydroxy-quinone, an oxidative product of cannabidiol, on the hepatic microsomal drug-metabolizing enzymes of mice.

Cannabidiol hydroxy-quinone (CBDHQ) was identified as an air oxidation product of cannabidiol (CBD). The in vitro incubation of mouse hepatic microsomes with CBDHQ resulted in a decrease of cytochrome P-450 content. CBDHQ inhibited the hepatic microsomal drug-metabolizing enzymes of mice. This inhibitory effect was stronger than that of CBD. CBDHQ (150 microM) inhibited aniline hydroxylase, p-nitroanisole O-demethylase and aminopyrine N-demethylase in the microsomes by 70, 52 and 77%, respectively, whereas the same concentration of CBD caused the inhibition by 39, 30 and 26%, respectively. CBDHQ (91.5 microM) significantly decreased total heme content by 21% and free SH groups by 11% in the microsomes. The results indicate that CBDHQ, which is an oxidation product of CBD, inhibits the hepatic microsomal drug-metabolizing enzymes through the decrease of cytochrome P-450 content.

Animals↗

PubMed1991

Synthesis and pharmacological activity of sulfate conjugates at 6-position of N-substituted normorphine derivatives.

Three pairs of N-substituted normorphine derivatives and the sulfate conjugates at the 6-position were tested for the analgesic and antagonistic activities and the development of physical dependence in mice. The compounds examined were nalorphine, nalorphine-6-sulfate (N-6-S), N-cyclopropylmethylnormorphine (CPN), N-cyclopropylmethylnormorphine-6-sulfate (C-6-S), N-dimethylallylnormorphine (DMN) and N-dimethylallylnormorphine-6-sulfate (D-6-S). The latter two pairs were newly synthesized. The analgesic activity of C-6-S and D-6-S was equipotent to that of CPN and DMN by the acetic acid writhing test on the s.c. injection, and the activity of N-6-S was about 2 times more potent than that of nalorphine. The antagonistic activity of N-6-S, C-6-S and D-6-S to morphine analgesia was higher than that of the parent compounds by the tail pinch test on i.c.v. injection. A withdrawal sign was seen in mice treated chronically with CPN, C-6-S and N-6-S by challenge with naloxone, whereas the mice treated with DMN, D-6-S and nalorphine showed no such sign. The effect of sulfation at the 6-position on the development of physical dependence was not well associated with the effect on agonistic and antagonistic activities.

Analgesics↗

PubMed1991

Structure-activity studies on triazolothienodiazepine derivatives as platelet-activating factor antagonists.

A series of triazolodiazepines was synthesized and evaluated for anti-platelet activating factor (PAF) activities. Structure-activity relationship (SAR) studies on this series revealed that the introduction of a methyl group into the 8-position of the thienodiazepine nucleus can lead to a lengthening of the duration of action. Introduction of a methyl group produced an asymmetric center and the enantiomers so formed were separated with an optical resolving column. In the in vitro assay system, the (+)-isomers displayed 50-200 times more potent anti-PAF activity than the (-)-isomers. After comparison of toxicology and pharmacokinetics, (+)-6-(2-chlorophenyl)-3- cyclopropanecarbonyl-8,11-dimethyl-2,3,4,5-tetrahydro-8H-pyrido[4' ,3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (35(+)-isomer, E6123) was selected from among the compounds synthesized as a candidate for clinical study.

Animals↗

PubMed1991

[Our drug metabolism studies during the last four decades].

The drug metabolism studies in which we have been engaging for about 40 years since 1952 are briefly reviewed in this paper. Our main efforts were initially made to elucidate the metabolic fates of various abused drugs including barbiturates, carbamates, opioids, amphetamines and cannabinoids in mammals from pharmacological and toxicological points of view. Among the interesting findings obtained from these studies, the most remarkable one was that morphine-6-glucuronide, a minor metabolite of morphine, has much stronger analgesic activity than morphine. Recently we have also been interested in clarifying the enzyme system involved in the metabolic pathways of the above drugs. Several cytochrome P-450 isozymes were thus purified from the liver microsomes of mammals and their role in oxygenation of amphetamines and cannabinoids were elucidated. The finding that MALDO (microsomal aldehyde oxygenase), a purified P-450 isozyme, could catalyze an oxidation of lipid-soluble aldehydes to the corresponding carboxylic acids was most noticeable. Metabolic and toxicologic studies on furylfuramide (AF-2) and polychlorinated biphenyl (PCB) have also been performed using rats and other animal species, and some interesting results were obtained.

Amphetamines↗

PubMed1991

A case of Graves' disease with false hyperthyrotropinemia who developed silent thyroiditis.

We encountered a patient who developed silent thyroiditis during the course of Graves' disease. The diagnosis of silent thyroiditis was made on the basis of a low thyroidal 131I uptake, no response to the thyrotropin releasing hormone (TRH) test, and subsequent hypothyroidism despite the presence of high titers of thyrotropin (TSH) receptor antibody (TRAb) and thyroid stimulating antibody (TSAb). The patient, in addition, had a discrepancy between serum TSH and thyroid hormone values. This was due to the presence of interfering substances that react to mouse IgG in the sera since serum TSH levels were decreased in a dose dependent manner by the addition of increasing amounts of mouse IgG to the sera. It should therefore be noted that silent thyroiditis can develop in patients with Graves' disease. Furthermore, clinicians should be aware that two-site immunoassay kits that use mouse monoclonal antibodies are subject to interference by some substances, possibly antibodies which react to mouse IgG.

Adult↗

PubMed1991

[Effect of cigarette smoking and/or N-bis(2-hydroxypropyl)nitrosamine (DHPN) on the development of lung and pleural tumors in rats induced by administration of asbestos].

Occupationally induced lung cancer and mesothelioma have long been attributed to asbestos and moreover, several epidemiological studies have indicated a co-carcinogenic effect of cigarette smoking on the incidence of lung cancer in asbestos workers. The aim of the present study was to investigate the co-carcinogenic effects of asbestos and other carcinogens with emphasis placed on determining the effects of cigarette smoking on the incidence of asbestos induced carcinomas. Doses of 15 mg of chrysotile asbestos were administered intratracheally to Wistar rats alone and in conjunction with N-bis(hydroxypropyl)nitrosamine (DHPN) and/or cigarette smoking. DHPN at dose of 1 g/kg/B.W. was injected three times intraperitoneally, and the subject animals were exposed to smoke from 10 cigarettes per day, six days a week, for their entire life span. As a result, lung carcinomas were induced in one out of the 31 rats receiving only asbestos. Lung tumors were induced at a much higher incidence in the groups receiving DHPN alone and in conjunction with asbestos: of the 37 rats treated with DHPN alone 19 (51.4%) developed lung tumors, whereas those receiving asbestos as well showed an incidence of 68.4% (23/38) of carcinomas. The development of lung carcinomas (including adenocarcinomas, epidermoid carcinomas, anaplastic carcinomas, and combined carcinomas) was seen in 8 (21.6%) out of the 37 rats receiving DHPN alone and in 23 (60.5%) out of the 38 rats receiving asbestos as well. The incidence of lung carcinoma was significantly increased in combined treatment with asbestos than DHPN alone. In the group receiving asbestos in combination with cigarette smoke, 4 (13.8%) out of the 29 rats developed lung carcinomas, but these carcinomas were more common than in the group receiving only asbestos. Moreover, in the group administered asbestos, DHPN and smoking combined, lung tumors developed in 18 (62.1%) out of the 29, 15 (51.7%) of which proved to be malignant. Mesothelioma (pleura) was induced in three groups in the following combinations: DHPN plus asbestos, 8/38 (21.1%); smoking plus asbestos, 2/29 (6.9%); and smoking, DHPN and asbestos, 4/29 (13.8%). These tumors were extensively located, that is, on the parietal pleura, visceral pleura, epicardium and diaphragm surface. However, mesothelioma was not induced by asbestos alone nor by DHPN alone. Carcinogenicity of asbestos for pleural tumors was significantly promoted by combined treatment with DHPN to an extent greater than DHPN alone. It should be noted that asbestos plus smoking resulted in a higher incidence of mesothelioma than asbestos alone.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenocarcinoma↗

PubMed1991

A novel metabolite of strychnine, 22-hydroxystrychnine.

1. An unknown metabolite of strychnine termed M-5 was isolated, from an incubation mixture using guinea pig liver microsomes, by repeated preparative t.l.c. 2. The structure of M-5 was shown to be 22-hydroxystrychnine by mass, n.m.r. and i.r. spectrometry. 3. 22-Hydroxystrychnine is a stable enol, a unique metabolite possessing a hydroxyl group on the double bond of the alicylic moiety.

Animals↗

PubMed1991

Metabolism in vivo of the tropane alkaloid, scopolamine, in several mammalian species.

1. In vivo metabolism of scopolamine was studied in rats, mice, guinea pigs and rabbits. The structures of eight urinary metabolites including unchanged drug were elucidated by mass and nuclear magnetic resonance spectrometry. Determination of these metabolites was achieved by a g.l.c. method using a semi-capillary column. 2. The major metabolites in rats were the three phenolic metabolites, p-hydroxy-, m-hydroxy- and p-hydroxy-m-methoxy-scopolamine. 3. Significant intra-species difference of the metabolism was observed in rabbits. Tropic acid was the major metabolite in two rabbits out of three, while the other rabbit excreted mainly unchanged scopolamine, accompanied by five metabolites. Tropic acid was also the major metabolite in guinea pigs, but was of minor importance in mice. 4. The dehydrated metabolites, aposcopolamine and aponorscopolamine, were abundantly excreted in guinea pigs, moderately in mice, and least in rabbits and rats. 5. Excretion of glucuronide conjugates of scopolamine and norscopolamine were high in mice compared with other species. On the other hand, phenolic metabolites in rat urine; and tropic acid in rabbit and guinea pig urine, were excreted as the free forms. 6. These results indicate that scopolamine metabolism is highly species-specific.

Animals↗

PubMed1991

[Ultrastructural study of the blood-testis barrier in rat by the lanthanum method].

Ultrastructural changes of the testes in 35-week-old WBN/Kob rats were investigated using the lanthanum-tracer method. Tissues were cut and fixed with a solution containing 1% lanthanum and 2% glutaraldehyde in a 0.1 M sodium cacodylate buffer at pH 7.8 and with a solution of 2% osmium and 1% lanthanum in a 0.1 M sodium cacodylate buffer. Ultrathin sections of epoxy resin-embedded specimens were stained with uranyl acetate and lead citrate and observed into a JEM-100CXS JEOL transmission electron microscope. The remnants of each testis were fixed in Bouin's fixative, and observed light-microscopically, where almost all seminiferous tubules in all of the six testes were found to be severely atrophied. Electron microscopically, lanthanum pigments were limited in the Sertoli cell tight junctions of the seminiferous tubules even in the severely atrophied tubules. In conclusion, it is unlikely that the testicular atrophy in WBN/Kob rats is attributable to dysfunction of the blood-testis barrier.

Animals↗

PubMed1991

[Pharmacokinetic study of adriamycin in the emulsion mixed with lipiodol-difference resulting from composition and methods of preparation, and behavior after mesenteric arterial injection in rat].

We experimentally investigated the pharmacokinetics of adriamycin (ADM) in a similar of transcatheter arterial chemoembolization therapy (TAE) of hepatocellular carcinoma using emulsion of lipiodol (Lp) mixed with ADM followed by gelatin sponge, and the difference resulting from composition and method of preparation of the emulsion as well as behavior after mesenteric arterial injection in rat. In in vitro study, the emulsion with iopamidol (iopamiron 300 : IP) was more stable than with amidotrizoic acid (60% Urografin : UG). The highest stability was found in the mixing ratio of Lp. IP and distilled water at 1 : 0.42 : 0.08. Frequent pumping also made the emulsion more stable. But in optimally composed emulsion, pumping 20 or 50 times made no difference in the stability during 30 min. which may be longer than the time from preparation to injection time of the emulsion in clinical application. After injection of the emulsion into the mesenteric artery which may simulate injection into the hepatic artery in hepatocellular carcinoma, the arterial blood flow was suspended. In the peripheral arteries the emulsion separated into two phases of Lp and ADM solution, forming striped pattern, and Lp embolization of the peripheral artery persisted for over 45 min. while ADM extravasated. These findings suggest that after Lp-TAE, Lp maintains an embolizing effect while ADM penetrates into the surrounding tumor tissue, and that this is an underlying mechanism for the anti-cancer effect of Lp-TAE.

Animals↗

PubMed1991

Image analysis by electron microscopy of two-dimensional crystals developed on a mercury surface of chaperonin from Thermus thermophilus.

Two-dimensional crystals of functional chaperonin molecules, which are protein complexes of cpn60 and cpn10, isolated from Thermus thermophilus were prepared on a mercury surface under oxygen atmosphere and were observed by electron microscope after transferring them to carbon coated specimen grids. The crystals showed the hexagonal lattice with unit cell dimensions of a = b = 12.4 nm and gamma = 120 degrees. The averaged image at a 3 nm resolution of the chaperonin has a doughnut-like shape which has seven peripheral masses and a central cavity. Preincubation of the chaperonin with MgATP changed the mobility in non-denaturating PAGE but did not cause distinguishable change of shape. The location of cpn10 in the chaperonin molecule is discussed.

Bacterial Proteins↗

PubMed1991

[Coronary collateral vessels during the early period of acute myocardial infarction: their development].

The aim of this study was to investigate the incidence and development of coronary collateral circulations in patients with acute myocardial infarction (AMI). We categorized 165 patients with persistent 100% occlusion of the infarct-related artery into 6 groups according to the time from the onset of AMI to angiography. Group I consisted of 55 patients evaluated within 6 hours after the onset of AMI; Group II, 28 patients, between 6 and 12 hours after the onset; Group III, 12 patients, between 12 and 24 hours after the onset; Group IV, 11 patients, between 2 and 13 days after infarction; Group V, 46 patients, between 14 and 44 days after infarction; and Group VI, 13 patients, more than 45 days after infarction. Collateral vessels were applied a numerical score between 0 and 3 according to the degree of opacification of the native vessel distal to the occlusion. In 58%, 79%, 67%, 73%, 89%, and 92%, patients of Groups I to VI had evidence of collateral vessels, respectively. Well-developed collaterals were observed in 24% of Group I compared with 50%, 58%, 55%, 73% and 69% of patients in Groups II to VI, respectively. The mean coronary collateral scores were 0.9 +/- 0.1, 1.4 +/- 0.2, 1.4 +/- 0.3, 1.6 +/- 0.4, 2.0 +/- 0.2 and 2.2 +/- 0.3 for Groups I to VI, respectively. Patients with preinfarction angina had more well-developed collateral circulations than did patients without it, however, there was no significant correlation between the duration of previous angina and extent of coronary collaterals.

Adult↗

PubMed1991

[Development of slow releasing anticancer drug based with absorbable biomaterial chitin].

To have a comparatively more slowly releasing anticancer drug with effectiveness, Plachitin was prepared by chemical combination of CDDP and chitin (poly-N-acetyl-D-glucosamine). Chitin is absorbed by the living body over several months. To investigate the slow releasing property, it was implanted in thigh muscle of mice and rabbit. Pt level in different organs and in urine was measured at regular intervals. Pt level in implanted muscles was higher in comparison to low serum level in mice. It was released slowly over 1 to 2 months in mice, whereas in rabbit it took about three weeks. Pt releasing period of the Plachitin was different according to the adopted method of implantation. Anticancer effect of Plachitin was investigated by injecting 180 sarcoma cells in mouse peritoneal cavity and subsequent implantation of Plachitin. In control groups chitin was used instead of Plachitin. The survival rate of mice in the Plachitin group after 14 days was higher than in the chitin group, and the anticancer effect of the Plachitin was confirmed.

Absorption↗

PubMed1991

[Toxicological assessment of 2,5,2',5'-tetrachlorobiphenyl and its major metabolite, 3-hydroxy-2,5,2',5'-tetrachlorobiphenyl in rats].

We observed previously that polychlorinated biphenyl (PCB) could be classified to two groups, 3-methylcholanthrene (MC)-type and phenobarbital (PB)-type, in term of inducibility of the hepatic enzymes. MC-type PCBs such as 3,4,3',4'-tetrachlorobiphenyl (TCB), 3,4,5,3',4'-pentachlorobiphenyl (PenCB) and 3,4,5,3',4',5'-hexachlorobiphenyl (HexCB) exhibited high acute toxicity in parallel with their induction ability of microsomal benzo[a]pyrene 3-hydroxylase and cytosolic DT-diaphorase. On the contrary, PB-type PCBs such as 2,5,2',5'-TCB and 2,4,5,2',4',5'-HexCB which induce microsomal benzphetamine N-demethylase and NADPH-cytochrome P-450 reductase activities showed virtually no or very low toxicity. In the present study, we examined effects of 2,5,2',5'-TCB and its major metabolite 3-hydroxy-2,5,2',5'-TCB on body weight gain, organ weights and activities of hepatic enzymes in rats and assessed acute toxicity of these compounds. As the results, in both 2,5,2',5'-TCB and 3-hydroxy-2,5,2',5'-TCB groups, the body weights were increased during the experiment, but the rate of growth was significantly suppressed after 3 days. Significant hypertrophy of the liver and decrease of total liver lipid content were observed in 2,5,2',5'-TCB group, but the atrophy of spleen and thymus was not affected in both groups. On the other hand, in 2,5,2',5'-TCB group, benzo[a]pyrene 3-hydroxylase and benzphetamine N-demethylase activities were increased to 2. 4-fold and 1.5-fold, respectively, but were not increased in 3-hydroxy-2,5,2',5'-TCB group. After injection of 2,5,2',5'-TCB, 45% of the dose was excreted as 3-hydroxy-2,5,2',5'-TCB in feces for 5 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

[Acute toxicity, inductive effects of liver enzymes and distribution in the liver of 1,2,3,7,8-pentachlorodibenzo-p-dioxin in rats].

Acute toxicity, inductive effects of liver enzymes and liver persistency of 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PenCDD) were compared with those of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) using male Wistar rats. 1,2,3,7,8-PenCDD treatment at a dose of 0.1 mumol/kg resulted in significant depression of growth of rats from a day to 28 days after treatment. However, the effect was relatively less than that of 2,3,7,8-TCDD. On 5 days, similarly to 2,3,7,8-TCDD-treated group, liver hypertrophy and thymic atrophy were observed in 1,2,3,7,8-PenCDD-treated groups. In addition, 1,2,3,7,8-PenCDD showed potent 3-methylcholanthrene-type inducing ability. For example, the activities of benzo(a)pyrene 3-hydroxylase and DT-diaphorase were 25-fold and 10-fold of control, respectively. On 30 days, about 50% of the inductive effects on 5 days were maintained in both 1,2,3,7,8-PenCDD- and 2,3,7,8-TCDD-treated groups. Amount of 1,2,3,7,8-PenCDD distributed to the liver on 5 days was about 80-90% of dose and was about 1.5 times greater than that of 2,3,7,8-TCDD. About 50% of dose of 1,2,3,7,8-PenCDD remained even on 30 days after treatment. From these results, it is suggested that 1,2,3,7,8-PenCDD possessing the potent acute toxicity comparable to 2,3,7,8-TCDD and higher persistency in the liver might be more important than 2,3,7,8-TCDD in terms of the chronic toxicity.

Animals↗

PubMed1991

[Studies on distribution and excretion of squalane in dogs administered for 2 weeks].

In the previous papers, we demonstrated, by using rats, that squalane (2,6,10,15,19, 23-hexamethyltetracosane) could stimulate the fecal excretion of 2,3,4,7,8-pentachlorodibenzofuran, the most important etiologic agent of Yusho, which was accumulated in the body of rat. We also reported that, in rats and dogs, squalane did not show any appreciable toxic signs during 3-month treatment, though a part of squalane was absorbed from gastrointestinal tract of dogs. In the present paper, we have investigated the elimination of absorbed squalane in beagle dogs. During the treatment with squalane orally at a dose of 1200 mg/kg/day for 14 days, the fecal excretion of squalane per day was 65-90% of the daily dose. After the treatment (on the day 14), squalane levels in blood and hair were about 30 ppm and 14640 ppm, respectively. On the day 56 after the first dosing, squalane was not detected in blood. On the day 70, squalane level in hair was reduced to about 1% of that on the day 14. Squalane levels in skin, liver, adipose tissue and small intestine on the day 70 were also reduced compared with that on the day 42. Moreover, small amount of squalane was still excreted into feces from the day 15 to the day 70. These results suggested that absorbed squalane was gradually excreted through feces and skin in dogs.

Administration, Oral↗

PubMed1991

[Chronic hemorrhagic empyema developed in thirty three years after the right pneumonectomy--a case report].

A 55-year-old man was admitted because of exertional dyspnea. He had the right pneumonectomy thirty three years ago. Chest X-ray showed the mediastinal shift to the left. And chest CT scan showed right intrathoracic mass. The bloody pleural effusion was aspirated (Hb 9.4 g/dl) and its examination revealed Staphylococcus epidermidis. We resected the empyema cavity. During the operation, massive bleeding was experienced (total 23200 ml). Pathologically, micro blood vessels were marked in the organized hematomas and the pleura. Chronic hemorrhagic empyema is a specific type of chronic empyemas and it is dangerous to remove of the hematomas because of massive bleeding.

Chronic Disease↗