Biomedical subjects
Publications and source records attributed to M Okada.
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Subacute toxicity and its recovery of bestatin (NK421) was studied on both sexes of 34 Beagle dogs. At dose levels of 600, 240, 96 and 38.4 mg/kg, NK421 was administered orally to dogs for 90 successive days. The control group was treated orally with 2 g/dog of corn starch. Each group was constituted of 3 males and 3 females, and 2 males and 2 females were added to the 240 mg/kg group for the recovery test for 35 days. As general symptoms, loss of appetite, vomiting, abnormal feces (loose stool, diarrhea, mucous stool), eye mucus, decoloration of the visible mucous membrance and unkempt fur were observed slightly and almost dose-dependently in the group dosed with more than 96 mg/kg. Body weight decreased with the passage of time in the 600 and 240 mg/kg groups, but no death appeared in any group. In correlation with general signs, slight anemia was seen hematologically, and the increased alkaline phosphatase activity and the decreased albumin ratio in serum protein fraction were observed biochemically. The slight abnormal findings of bone marrow, spleen and liver were also demonstrated histopathologically. All the above findings disappeared during the recovery period. The maximum non-toxic dose of NK421 in this study is estimated to be 38.4 mg/kg in dogs.
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We developed a new simple enzymatic assay method for measuring urinary polyamines (total amount of putrescine, spermidine, and cadaverine), using an acylpolyamine amidohydrolase and a putrescine oxidase. First conjugated polyamines (putrescine, spermidine, and cadaverine) in urine were hydrolyzed by incubation with an acylpolyamine amidohydrolase at 30 degrees for 1 hr. then, free polyamines were separated by cation-exchange chromatography and incubated with a putrescine oxidase at 30 degrees for 30 min. Hydrogen peroxide formed in this reaction was measured spectrophotometrically (at 514 nm). Polyamine levels in urine were determined in 70 normal subjects, 124 patients with cancer, and 52 patients with diseases other than cancer. Elevation above 3 S.D.s of the normal mean was found in 90 (72.6%) of the 124 patients with cancer and in 6 (11.5%) of the 52 patients with diseases other than cancer. Serial studies in 19 patients with cancer indicated that polyamines in urine were reduced after successful surgery. Our new method is simple and rapid and therefore very useful for routine clinical application. Moreover, our data indicate that the determination of polyamine levels is useful as a marker of disease activity in patients with cancer.
Species variations in response to urinary bladder carcinogens, N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN), N-ethyl-N-(4-hydroxybutyl)nitrosamine (EHBN), and N,N-dibutylnitrosamine (DBN), were investigated in several animal species from the metabolic point of view. Since N-butyl-N-(3-carboxypropyl) nitrosamine (BCPN) and N-ethyl-N-(3-carboxypropyl) nitrosamine (ECPN) had been found to be the principal urinary metabolites which are responsible for the induction of bladder tumors by BBN or DBN and EHBN, respectively, in rats, acidic urinary metabolites with the N-nitroso moiety were isolated and determined by a colorimetric method after oral administration of these nitrosamines to rats, mice, hamsters, guinea pigs, and dogs. Qualitatively almost no species differences were observed among these animals in regard to the urinary metabolites except in the case of mice, in which the glycine conjugate of BCPN was isolated from the urine and identified as the principal metabolite of BBN and DBN. However, appreciable quantitative differences in the urinary excretion of BCPN or ECPN were found among these animal species, indicating that the differences in the susceptibilities of different animal species to urinary bladder carcinogenesis induced by BBN, DBN and EHBN may be closely related to the different extents of urinary excretion of the active metabolites of these nitrosamines.
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A simple and sensitive procedure is described for the quantitative determination of N-butyl-N-(3-carboxypropyl)nitrosamine (BCPN), the principal metabolite of the bladder carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine (BHBN-4), in urine. BCPN was analyzed by gas-liquid chromatography as its methyl ester after extraction with ethyl acetate from urine followed by esterification with diazomethane. Species and strain variations in susceptibility to bladder carcinogenesis induced by BHBN-4 are discussed in relation to the urinary excretions of BCPN, determined by the new procedure, after oral administration of the compound to rats (4 strains), mice, hamsters, and guinea pigs at a dose approximately equal to the daily dose used in chronic carcinogenicity assay.
The serum concentration of geranylgeranylacetone (GGA) was estimated in four patients with peptic ulcer following oral administration of a 100-mg dose. The area under the serum concentration-time curve (AUC) after oral dosing of the patients 30 min after a meal was 30- to 45-fold larger than that in the fasted state. Distribution of GGA in the stomach removed surgically from the patients was also examined after oral administration of 50 mg thrice daily for 1-13 days prior to surgery. The tissue level of GGA in the ulcer region was higher than that in the surrounding normal region.
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Cytotoxic effects on MDBK cells of various 3-substituted propylamines, including spermine and spermidine, were tested in culture in the presence of calf serum, and the possible mode of action was studied from the viewpoint of oxidative deamination leading to acrolein formation. The compounds were roughly classified in two groups with IC50 values of 0.1 and 0.4 mM under the conditions used. Phenyl derivatives of 3-substituted propylamines, 3-benzylaminopropylamine, and polyamines were included in the first group with IC50 values of 0.1 mM, and acrolein was liberated from these compounds after incubation with bovine plasma amine oxidase. Alkyl derivatives of 3-substituted propylamines (with IC50 values of 0.4 mM), on the other hand, were unable to release acrolein after the oxidative deamination, which was further confirmed by a lack of liberation of acrolein from the authentic 3-butoxypropanal. These observations indicated that both the acrolein originating from the 3-substituted propanals, and the propanal as such, were possibly involved in manifestation of the cytotoxicity of the 3-substituted propylamines. Thus, spermine and spermidine may exert their cytotoxic effects on the cells in vitro by a combination of two mechanisms involving acrolein and oxidized polyamines.
The transmission of adult T cell leukemia virus, a human retrovirus, into fresh leukocytes from normal humans was examined. One of three virus-carrying cell lines, tested after being subjected to lethal x-irradiation, consistently transformed leukocytes from adult peripheral blood and umbilical cord blood. All the transformed cell lines expressed adult T cell leukemia virus-associated antigen, but transformed lines originating from adult and umbilical cord blood exhibited T cell and non-T, non-B cell surface natures, respectively. Efforts to transform human leukocytes with cell-free virus were unsuccessful.
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Dipeptidyl-aminopeptidase IV (DAP-IV) was purified 850 fold with a yield of 16.5% from human kidney cortex. Only two chromatographic procedures of DEAE-cellulose and anti DAP-IV Sepharose were used. The purified enzyme was shown to be homogeneous by polyacrylamide gel electrophoresis in the presence of sodium dodecylsulfate. Among various substrates with the structure of X-Y-p-nitroanilide, Lys-Pro-Gly-Pro- and Arg-Pro-p-nitroanilides were hydrolyzed very fast by DAP-IV. Optimum pH of DAP-IV in human kidney was pH 8.7, Km value for Gly-Pro-pNA was 2.51 +/- 0.01 x 10(-4) M and V max was 66.6 +/- 0.7 mumol/min/mg protein. Diisopropylfluorophosphate completely inhibited DAP-IV at 0.1 mM. However, the enzyme was almost unaffected by N-ethylmaleimide, p-chloromercuribenzoate, iodoacetate, phenylmethylsulfonylfluoride, and several metals. The amino acid composition of DAP-IV purified from human kidney was similar to that of DAP-IV purified from pig kidney, liver and intestine. These results indicate that the properties of DAP-IV purified from human kidney are almost same as those from pig kidney.