Biomedical subjects
Publications and source records attributed to C Nagata.
The epoxide hydratase inhibitor, 1,1,1-trichloro-2,3-propene oxide (TCPO) in combination with benzo[a]pyrene (B[a]P) was injected s.c. in ddN mice. The formation of fibrosarcoma by B[a]P was slightly accelerated at low dose of TCPO, and remarkably inhibited at high dose of TCPO. The correlation of carcinogenesis with B[a]P metabolism was discussed.
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By means of the molecular orbital method, the reaction mechanism of the specific and irreversible enzyme inhibitors, such as cycloserine, L-2-amino-4-methoxy-trans-3-butenoic acid (AMB), and vinylglycine (2-amino-3-butenoic acid), was studied. Firstly, it was attempted to know which pathway is probable between the transamination process and the isomerization one. By comparing the energy increments for these two reactions, the transamination reaction was predicted to be energetically favorable, supporting the proposition of Rando. Upon complexing with the coenzyme-pyridoxal moiety of alanine racemase or aminotransferase, the reactivity of the inhibitors toward the nucleophile was found to be considerably increased due to the lowering of the lowest unoccupied molecular orbital (LUMO), and this was considered to be the reason why the inhibitors become bound with the enzyme irreversibly. The LUMO of aspartate, substrate of aspartate aminotransferase, is higher than those of the inhibitors in the free state, as well as in the pyridoxal-linked state. This difference in the energy of the molecular orbital between substrate and inhibitors was considered to be correlated with the difference in the complex-forming properties of these compounds toward the nucleophile in the enzyme.
The formation of Thy-Thy in DNA in the presence of tyramine, tyrosine and tyrosine-containing peptides such as Lys-Tyr and Lys-Tyr-Lys was studied with monochromatic UV irradiation. The formation of Thy-Thy by UV irradiation was enhanced in the presence of these compounds. The action spectrum of the photosensitization has a peak near 280 nm corresponding to the absorption spectrum of tyrosine. The triplet quencher reduced the sensitization substantially. The sensitization in native DNA was more than six times larger than that in denatured DNA. increasing the concentration of salts suppressed the sensitization. The nature of the interaction between DNA and the sensitizer is discussed.
Crystals of 6-oxybenzo(a)pyrene free radical, formed chemically from the hydroxy derivative of the carcinogen benzo(a)pyrene, can be solubilized in aqueous solutions of DNA and of caffeine. ESR spectral evidence indicate that the radicals exist as dispersed monomers associated with DNA and with caffeine. Comparison of NMR spin-lattice and spin-spin relaxation times in the protons of caffeine has given direct evidence that a part of the unpaired electron (at least 10(-4)) is transferred from the radical to the associated caffeine molecule. Simple consideration of Mulliken's charge transfer theory, however, leads to the conclusion that the intermolecular charge transfer is not likely to be a major source of stabilization energy of the complex.
For the first time, change in the proton longitudinal relaxation times (T1) of rat tissues has been examined throughout the whole process of azo-dye hepatocarcinogenesis. Two maxima of the T1 values were observed for liver, on Day 60 and after Day 120, and these changes correlated well with the changes in water content. The first peak was ascribed to the immature hepatocytes of hyperplastic nodules, and the second peak to the developed hepatoma cells. The significance of the change in T1 values as a preneoplastic change is discussed.
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The effect of phenethyl alcohol on DNA synthesis was examined using several in vitro systems of Escherichia coli H560; i.e., ether-treated cells, membrane fractions and folded chromosomes fortified with DNA polymerase. In all systems, the incorporation of deoxyribonucleotides was much reduced for the phenethyl alcohol-treated cells compared with the non-treated cells. The total activity of DNA polymerases in polA1 cells (mostly DNA polymerase II) was not impaired for the phenethyl alcohol-treated cells and the reduction of the rate of DNA synthesis in vitro was ascribed to the reduction of the chromosomal template activity which was related to trypsin sensitive protein components. The analysis of chromosomes from the phenethyl alcohol-treated cells revealed the remarkable reduction of a protein component of molecular weight approx. 58 000 in contrast with a protein component of molecular weight approx. 30 000.
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Argininosuccinate synthetase (EC 6.3.4.5) was immobilized on CNBr-activated Sepharose 4B. Properties of the immobilized enzyme are described and compared with those of the native enzyme. The immobilized enzyme was much more stable than the native enzyme at 37 degrees C. It was further stabilized in the presence of the assay reagents. The optimum pH of the immobilized enzyme shifted towards alkalinity (approximately 0.5 unit). The apparent Michaelis constants measured for the immobilized enzyme were not greatly different from those measured for the native enzyme. Urea formation from citrulline was confirmed in a continuous column reactor by the coimmobilized argininosuccinate synthetase, argininosuccinate lyase (EC 4.3.2.1), and arginase (EC 3.5.3.1).
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