The mechanism for oxidation of human oxyhemoglobin induced by ethopropazine was studied. The rate of methemoglobin formation followed second-order kinetics and became faster with an increase of pH. The methemoglobin formation was not inhibited by either catalase or superoxide dismutase. The increase of absorbance at 520 nm, which was attributed to the reduction of ferrocytochrome c, was not inhibited by superoxide dismutase. On the other hand, the decrease of absorbance at 550 nm which corresponded to the co-oxidation of ferrocytochrome c was inhibited by catalase. The oxidation of human oxyhemoglobin induced by ethopropazine seemed to occur through two electron reduction mechanism. In the initial step, a single electron transfers from ethopropazine to the bound dioxygen of oxyhemoglobin giving rise to (Fe²⁺-OO^-) and a semiquinone free radical. In the second step, a single electron transfers from the iron atom to the bound dioxygen producing hydrogen peroxide and methemoglobin. The two electron transfer mechanism giving rise to hydrogen peroxide and methemoglobin seems to give an important implication to the drug-induced methemoglobin formation and hemolysis of erythrocyte.

抄録全体を表示

Inhibitory effect of 24 triterpenoids from Cimicifuga spp. on lymphocyte blastformation with phytohemagglutinin (PHA) was studied. The results of this study provided a structure-activity relationship for potent suppressive activities. A hemiacetal group in the side chain, an oxygenated group in the C₁₂ position, a cyclopropane ring on the B ring and a double bond at the C_{7 (8)} position proved to be responsible for the activity. Cimicifugoside (I), which is endowed with all above mentioned functional groups to enhance the activity, was the strongest inhibitor of thymidine transport into PHA-stimulated lymphocytes. As little as 4 ng/ml cimicifugoside caused 50% inhibition of thymidine-³H uptake in the lymphocyte culture. Moreover, addition of the triterpenoid to mouse lymphosarcoma L-5178Y cell cultures resulted in a significant inhibition of transport of nucleosides into the cells, where neither cytotoxicity nor inhibition of the cell growth at higher concentration was observed. At same conditions, inhibitory activities of incorporation of leucine and glucosamine were not detected. These results indicate that the inhibition of thymidine uptake by cimicifugoside and its related compounds may not be due to the inhibition of DNA synthesis but on the membrane transport of nucleoside and/or nucleoside trapping mechanisms.

抄録全体を表示

To examine the possibility of utilizing albumin microspheres as drug-carriers, an in vitro release of 5-fluorouracil (5-FU) from albumin microspheres was examined and the effect of intraperitoneally injected drug-carrying microspheres on Ehrlich ascites carcinoma in mice was studied. In vitro release characteristics determined by dialysis experiments showed that 5-FU release continued over one week. We also noted that drug release in the peritoneum of ascites-bearing mice continued over one week and that their life-span increased. Furthermore, the microspheres were phagocytized in vivo by the ascites cells. Our results suggest that albumin microspheres containing 5-FU may represent an effective system of drug delivery with prolonged action.

抄録全体を表示

The biological fates of ethylparaben (EP) which has been widely used as a preservatives for the pharmaceutical preparations and foods, and p-hydroxybenzoic acid (HB) which is the parent compound of EP, were investigated at the dose of practical usage (2 mg/kg) in rats. Although both EP and HB were metabolized to glycine conjugate (M1), ester type glucuronide (M3) and sulfate (M4) of HB and excreted in the urine and bile, the excretion ratios were different as compared with the results of higher dose experiments carried out by other authors, and a route dependency was also found in the rate of excretion in the bile. The excretion data obtained in this study are shown as follows : In intravenous administration of EP, the excreted total activity was 91.3% per dose in the urine and 5.97% in the bile, and percentages per dose of the major metabolites excreted in the urine were 8.14% of HB, 39.6% of M1, 29.5% of M3 and 6.48% of M4. In intraduodenal administration of EP, the excreted total activity (83.5%) and the activity excreted as HB (3.51%) decreased compared with the intravenous administration. In the HB administration, the route dependency of the total activity was not found, but a decrease in the excretion of HB in the intraduodenal administration was found. The excretion of total radioactivity almost ceased by 5 hr and the biological halflives obtained from the β-phase of the sigma-minus plots of the metabolites excreted in the urine were 40-70 min. The result obtained in this study differ from those of other authors at the high dose experiments.

抄録全体を表示

Incubation of 2-hydroxyestradiol (1) with rat liver homogenate in the presence of Sadenosyl-L-methionine and Mg²⁺ gave two isomeric monomethyl ethers, 2-methoxyestradiol (2) and 2-hydroxyestradiol-3-methyl ether (3). The ratio of the 2-O-methyl ether to the 3-O-methyl ether formed was found to be dependent on hydrogen ion concentration of the medium. At pH 6.0, the ratio was about 3-4, which decreased gradually with increasing pH, and at pH>7.0, the ratio was approaching to unity. PH dependency upon the product ratio was significant when 2, 3, 17β-trihydroxyestra-1, 3, 5 (10)-trien-6-one (5) was used as a substrate, although the ratio was completely reversed in contrast with the result obtained with 2-hydroxyestradiol. At pH 6-7, the ratio of the 3-O-methyl ether (7) to 2-O-methyl ether (6) was about 6-8. With increasing pH of the medium, 2-O-methylation increased gradually, and at over pH 8.0 the ratio became constant at about 3. These results suggest that rat liver catechol O-methyltransferase catalyzes the transfer of the methyl group from S-adenosyl-L-methionine to more basic hydroxyl group of the two phenolic hydroxyl groups of estrogen catechols.

抄録全体を表示

Various purified saponins were examined for their lytic activities against mammalian erythrocytes and their activities to interact with liposomal membranes, and were classified into at least five categories according to their reactivities. 1. Digitonin, F-gitonin, dioscin and paris saponin Pa : These saponins showed hemolytic activity and induced permeability change in liposomal membranes containing cholesterol. The interaction of these saponins with cholesterol was "irreversible". The interaction was independent of acyl chain lengths of phosphatidylcholine. 2. Gracillin : This saponin showed hemolytic activity but did not induce permeability change of liposomal membrane with cholesterol, except those containing distearoyllecithin. The interaction of gracillin with cholesterol was "irreversible". 3. Akebia saponin B, C, P_D and P_G : These showed hemolytic activities and induced the permeability changes of liposomes with cholesterol. Their activities to induce permeability changes were affected by chain length of phosphatidylcholine. With increase of chain length, the sensitivity of liposomes toward these saponins decreased. The interaction of saponins with cholesterol was "reversible". 4. Chikusetsusaponin III : This saponin has a weak lytic activity against erythrocytes and has the activity to induce permeability change of liposomes without cholesterol. Cholesterol in the phosphatidylcholine liposomes depressed the sensitivity of the liposomal membrane to the saponin. 5. Chikusetsusaponin V and akebia saponin E and Pk : These compounds ("bisdesmosidisch") showed neither detectable activity to lyse erythrocytes nor to damage liposomal membranes. liposomal membranes.

抄録全体を表示

Enhanced delivery of bleomycin (BLM) into lymphatics by complexation with dextran sulfate was investigated following intramuscular and intragastric injection in rats. It was observed that the injection of the complex aqueous solution into muscle or stomach did not slow down the rate of disappearance from the site of injection. However, when the complex was protected from dissociation by incorporating into W/O emulsion system, intramuscular injection of BLM caused a slower disappearance from the tissue, and a more retarded plasma peak concentration than the complex aqueous solution or the emulsion system containing free BLM. Intragastric injection of the emulsion containing complex showed the most enhanced delivery of BLM into the regional lymph nodes. The results of this study suggest the exsistence of a special transport mechanism through which BLM is delivered together with dextran sulfate into lymphatics.

抄録全体を表示

The regional and developmental change in specific activity of 2', 3'-cyclic nucleotide 3'-phosphohydrolase (CNPase) and carbonic anhydrase (CAase) and influence of the neonatal treatment with 6-hydroxydopa (6-OHDOPA) were investigated in the rat. CNPase activity rapidly increased between days 5 and 20, slightly between days 20 and 70. CAase activity gradually increased during postnatal development. The activities of both enzymes were higher in the brain stem and diencephalon than in the cerebral cortex and the cerebellum of the developing and adult animal. The systemic injection of 6-OHDOPA at birth induced a significant decrease in CNPase activity in the neocortex of the adult but in all regions of the 5-day-old rat. On the other hand, the treatment produced a significant increase in CAase activity in the neocortex and paleocarotex of the developing and adult rat. The neonatal treatment with 6-OHDOPA appears to impair normal growth of the brain by interfering the interaction between neurons and glial cells in the rat brain.

抄録全体を表示

Fifty imidazo [4, 5-g] quinoline derivatives were synthesized and their antitumor activities were tested against Ehrlich ascites carcinoma, and mouse leukemias L-1210 and P388. These derivatives were administered intraperitoneally in the form of suspension. 1, 3-Dimethyl-1, 2, 5, 8-tetrahydro-2, 8-dioxoimidazo [4, 5-g] quinoline-7-carbohydroxamates with relatively small alkyl groups, ethyl (24), 2-butenyl (44), butyl (33) and vinyl (41) moiety, at the 5 position, were found to be highly effective against Ehrlich carcinoma (30-day survival≨67%). Three derivatives, compounds 41 and 44, and 1, 3-dimethyl-5-vinyl-1, 2, 5, 8-tetrahydro-2, 8-dioxoimidazo [4, 5-g] quinoline-7-carboxylic acid (15), increased the lifespan of mice bearing leukemia L-1210 to more than 50% over the control. Compounds 41 and 44 were also found to be active against mouse leukemia P388.

抄録全体を表示

There were pronounced interindividual differences in the plasma protein binding of 1-anilino-8-naphthalenesulfonate (ANS) and phenylbutazone in rats. A highly statistically significant positive correlation was observed between the free fraction of ANS and phenylbutazone (r=0.896, p<0.001), and the possibility of the application of ANS to a clinical test was discussed. Kinetic analysis of ANS binding to individual rat plasma revealed the presence of endogenous competitive inhibitors. Free fatty acids (FFA) were suggested for one of the endogenous inhibitors, since the free fraction of ANS and the FFA concentration were related with a correlation coefficient of 0.609 (p<0.001).

抄録全体を表示

Microsomal NADPH-cytochrome P-450 reductase (EC 1.6.2.4) and xanthine oxidase (EC 1.2.3.2) catalyzed the activation of antitumor antibiotic, mitomycin C, under anaerobic conditions. Under aerobic conditions, NADPH-cytochrome P-450 reductase catalyzed the quinone structure containing antitumor compound-dependent NADPH oxidation. With our previous results, the direct contribution of NADPH-cytochrome P-450 reductase to the quinone drug metabolism was generalized.

抄録全体を表示