Hidemasa Yamasaki

The mechanism of the reduction of cytochrome c by xanthine oxidase

Abstract 1. In the absence of an electron carrier the reduction of cytochrome c by milk xanthine oxidase (xanthine: O2 oxidoreductase, EC 1.2.3.2) requires molecular oxygen. However, the reduction takes place under anaerobic conditions in the presence of various electron carriers such as 2-methyl-1,4-naphthoquinone, 1,4-naphthoquinone, trinitrobenzenesulfonate and methylene blue. 2. Using 2-methyl-1,4-naphthoquinone as an electron carrier, a comparison was made of the direct reduction of cytochrome c in the presence of oxygen and the carrier-mediated reduction in the absence of oxygen. 3. The two reactions were found to differ in their pH dependency. The pH optimum for the oxygen-induced reduction was approx. 10.0 while that for the carrier-mediated reduction was 7.5. 4. In the presence of carrier, and in the absence of oxygen, one mole of hypoxanthine reduced 3.4–3.7 moles of cytochrome c. The presence of oxygen caused only a slight fall in this value. In the absence of carrier, however, 0.81–0.92 mole of cytochrome c was reduced per mole of hypoxanthine under aerobic conditions. 5. Catalase and Tiron markedly inhibited the oxygen-induced reduction but hardly affected the carrier-mediated reduction. 6. In the presence of sufficient 2-methyl-1,4-naphthoquinone, the carrier-mediated reaction was predominant even under aerobic conditions.

PREPARATION AND PROPERTIES OF N-(RING)-RIBOSYLHISTAMINE DERIVATIVES.

Abstract The preparation, purification and characterization of histamine adenine dinucleotide, histamine mononucleotide and histamine nucleoside are described. All of these compounds show no histamine-like activity as proved by tests on the contraction of guinea pig ileum, the fall in blood pressure of the cat and on the local accumulation of circulating dye in guinea pig skin. Histamine nucleoside is easily cleaved by nucleoside hydrolase from Lactobacillus delbrueckii . However, the phosphorolytic cleavage of nucleoside and the reverse reaction are not demonstrable with the mammalian nucleoside phosphorylase.

Sdudies on the combined actions of alkylresorcinols as an anthelmintic.

On the combinations between 4-cyclohexyl-6-chlororesorcinol. (C. H. C. R.) and 4-n-octyl-6-chlororesorcinol (O. C. R.), C. H. C. R. and 4-n-octylresorcinol (O. R.), remarkable potentiation of the efficiency in combating ascaris was observed in certain ratio of mixture. The most efficient ratio of mixture, in both cases lay within the rang e of from 90% of C. H. C. R. contained. Oral toxicity tomice, local irritant action (examined on conjunctiva of rabbits, human tongues and gastric mucosa of dogs and also clinical side effects of these mixtures of most efficatious ratios did not significantly differ from those of C. H. C. R., the fact revealing no potentiation in such aspects. These mixtures proved, to be superior in anthelmintic efficacy and less toxic and less irritant than hexylresorcinol. Some physical changes such as a fall of melting, point and a lowering of interfacial tension of solution are supposed to be important factors in the mechanism of anthelmintic potentiation of these mixtures.

SOME ANTHELMINTIC PROPERTIES OF OCTYLCHLORORESORCINOL AGAINST ASCARIS LUMBRICOIDES IN MAN

Among a series of highly effective alkylchlororesorcinols against Ascaris luinbricoidgs, effects of which were discovered in our laboratory in 1948/49 (1, 2, 3) as a result of systematic studies with the co-operation of Dr. Tomita and Dr. Uyeo (4, 5, 6) of the Pharmaceutical Institute of Kyoto University in the synthesis of these compounds, a member that proved lowest in toxicity as well as in local irritant action was 4-n-octyl-6-chlororesorcinol. Ashikaga (1) of our laboratory first studied clinical effects of this compound in 1949 and obtained satisfactory results, which, in due time, were confirmed by Hattori and his co-workers (7). For about a year after this there came forth no significant report on clinical studies of this compound. But, last year, reports by Hattori et al. (8) and by Inouye et al. (9) came out, and according to these reports, the efficacy of the compound seems to have suffered rather a severe diminution. Not only that but also, we too have discovered, after having examined two kinds of tablets of this compound prepared by a pharmaceutical Co., that, to our surprise, there occurred a great deal of deterioration in its efficacy compared to earlier data. Whereupon, we again examined the efficacy of three samples of crystalline octylchlororesorcinol that were synthetized since its first trial and found every one of them to be unsatisfactory. In order to know to what causes this change could be ascribed, we decided to launch our researches in the following two directions: Firstly, to find out if any drug-resistance against this compound had been developed on the part of Ascaris under the recent circumstances in which hexylresorcinol became so popular and widely used, and secondly, to re-investigate the problems concerned with the purity of the compound. On the first point, however, recent Mannamis investigations (10) of actual cases revealed no convincing evidence of manifestations of drug-resistance that would explain the above-mentioned change in the efficacy. In respect to the second point, however, the analysis performed by Tomita et al. of Kyoto University showed, oddly enough, that the one lower in efficacy to be the purer. Puzzled by these findings, we finally asked there for a new sample of this drug to be prepared under the same condition as when we received it for the first time. The newly prepared crystals, when tested, proved to be much more efficacious than the other low-efficacy crystals, though the former had lower melting point than the latter. Confronted with these facts, it became necessary for the authors to clarify as to what difference or differences in the properties of these two samples, which are supposed to be alike, the distinct difference in the behavior of these samples could be attributed. In this paper, the authors tried to solve the problem by studying if there is any difference in the physical and chemical properties of all samples of octylchlororesorcinol that have been used in the clinical investigations and by comparing pharmacologic properties of the low-efficacy crystals with those of the newly prepared efficacious crystals.