Hidetoshi Yoshimura
Kyushu University
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Featured researches published by Hidetoshi Yoshimura.
Biochemical Pharmacology | 1973
Hidetoshi Yoshimura; Seiu Ida; Kazuta Oguri; Hisao Tsukamoto
Abstract To understand the potent analgesic action of morphine-6-glucuronide (M-6-G), which was reported previously to be a minor metabolite of morphine in several mammalian species, the penetration of this conjugate into the brain was investigated using 14 C-labeled compound. A similar study was also conducted with 14 C-morphine. These studies presented evidence that, although M-6-G was a highly polar conjugate, it can penetrate the blood brain barrier and react with the receptor of analgesic action without prior hydrolysis of the glucuronide linkage. It was further suggested that the lack of analgesic activity produced with morphine-3-glucuronide (M-3-G), a major metabolite of morphine, was attributable to its inability to react with the receptor, because it penetrates the brain as well as M-6-G.
Toxicology and Applied Pharmacology | 1981
Shinichi Yoshihara; Kiyoshi Nagata; Hidetoshi Yoshimura; Hiroaki Kuroki; Yoshito Masuda
Abstract Toxicological assessment of 13 individual polychlorinated dibenzofurans (PCDFs) with varying chlorine substitutions was made in young male Wistar rats. All the 9 congeners having at least three chlorine atoms in the ring positions at 2, 3, 7 and 8, such as 1,2,7,8-, 2,3,6,7-, and 2,3,7,8-tetrachlorodibenzofurans (TCDFs), 1,2,3,7,8-, 1,2,6,7,8-, 2,3,4,7,8-pentachlorodibenzofurans (PenCDFs), 1,2,3,4,6,7- and 1,2,3,4,7,8-hexachlorodibenzofurans (HCDFs), exhibited a typical 3-methylcholanthrene (MC)-type induction, i.e., a marked increase in activity of aryl hydrocarbon hydroxylase (AHH) and DT-diaphorase in the liver. The most potent congeners were 2,3,7,8-TCDF and 2,3,4,7,8-PenCDF, both of which significantly induced the AHH and DT-diaphorase even at a single dose of 1 μg/kg. On the contrary, the congeners having two or less chlorine atoms in the lateral ring positions, such as 2,8-dichlorodibenzofuran, 1,3,6,7- and 1,3,6,8-TCDFs, and 1,2,4,6,8-PenCDF, did not show any inductive effect on these hepatic enzymes at the single dose of 5 or 10 mg/kg. All the MC-type PCDFs except for 1,2,7,8-TCDF caused a marked atrophy of the thymus and a hypertrophy of the liver in rats, while no toxic signs were observed in animals treated with the congeners lacking the MC-type inducing ability. The ranking of toxic potencies of the MC-type PCDFs coincided well with their inducing abilities. The hepatic disposition of the congeners varied markedly. For example, 2,3,7,8-TCDF and 2,3,4,7,8-PenCDF showed an equipotent toxicity, however, the hepatic concentration of PenCDF was about 20-fold higher than that of TCDF. These results clearly indicate that the acute toxicity of PCDF congeners is well correlated with their MC-type inducibility, but not with their hepatic distribution.
Life Sciences | 1987
Kazuta Oguri; Isomi Yamada-Mori; Junko Shigezane; Takaaki Hirano; Hidetoshi Yoshimura
Effect of the modification of morphine and nalorphine by glucuronate and sulfate conjugations at the 3- and 6-positions on the binding to opioid receptors was examined in a particulate fraction of rat brain. Competing potencies of both drugs against [3H]morphine and [3H]leucine enkephalin bindings were extremely decreased by either glucuronate or sulfate conjugation at the 3-position. On the other hand, the potencies of morphine and nalorphine against [3H]leucine enkephalin binding were considerably enhanced by the conjugations at the 6-position, whereas the potencies against [3H]morphine binding were decreased. These altered interactions of the conjugates at the 6-position with the two ligands were attributed to their enhanced binding to delta-receptor and reduced binding to mu-receptor by Hill plot and modified Scatchard analysis. Resulted comparable and simultaneous interactions with mu- and delta- receptors were assumed to be a cause of the enhanced mu-receptor-directed analgesia of morphine and elevated same receptor-directed antagonistic effect of nalorphine, which have been found previously in our laboratory.
Archives of Biochemistry and Biophysics | 1976
Hidenari Shigematsu; Shigeru Yamano; Hidetoshi Yoshimura
Abstract Liver microsomes are known to contain enzyme systems catalyzing monooxygenation of many foreign compounds including O -dealkylation which require NADPH and oxygen. In the present study, O -deethylation of p -nitrophenetole with rabbit liver microsomes proceeds well with NADH instead of NADPH as a cofactor. When both NADH and NADPH are used, deethylation increases markedly. The NADH-dependent system was shown to be different from the NADPH- and the NADH plus NADPH-dependent systems in several ways. For instance, in addition to the difference in optimum pH and oxygen dependency, the NADH-dependent system is not inhibited by CO, whereas the other two systems are inhibited markedly. Pretreatment of rabbits with CoCl 2 decreases both the content of cytochrome P -450 and the NADPH-linked deethylase activity but changes neither the cytochrome b 5 content nor the NADH-linked deethylase activity. After administration of 3-methylcholanthrene to the rabbit, the NADH-dependent deethylation activity is not enhanced, but the other two activities increase about twofold. KCN, at a concentration of 10 −4 m , on the other hand, does not affect any of the three activities. These results strongly suggest the possible involvement of a new type of NADH-dependent oxygenase, which is different from cytochrome P -450 and cyanide-sensitive factor, in the deethylation of p -nitrophenetole with rabbit liver microsomes.
Life Sciences | 1972
Masa-aki Mori; Kazuta Oguri; Hidetoshi Yoshimura; Kyoichi Shimomura; Showa Ueki
Abstract Chemical synthesis of morphine-3- and -6-ethereal sulfate was accomplished, utilizing chlorosulfonic acid as sulfonating reagent. The analgesic effect of morphine-6-sulfate in mice was about same order of magnitude as that of morphine-6-glucuronide, being much higher in potency and longer in duration than that of morphine. On the other hand, no effect was observed with morphine-3-sulfate (20 mg/kg, s. c.). Morphine-6-sulfate, an active conjugate, could not be detected in the urine of cats injected with morphine by careful examination with thin-layer chromatography.
Chemosphere | 1986
Jun Kuroki; Nobuyuki Koga; Hidetoshi Yoshimura
The interaction of 2,3,4,7,8-pentachlorodibenzofuran (PenCDF) with cytochrome P-450 isozymes was studied in male Wistar rats using 14C-labeled PenCDF. Three forms of cytochrome P-450 isozymes, P-448 H, P-448 L and P-452, were purified to homogeneity from 14C-PenCDF-treated rat liver microsomes. The purified P-448 H contained 0.847 mole of PenCDF per mole of the hemoprotein, whereas the amounts of PenCDF bound to P-448 L and P-452 were far less than that to P-448 H. These results suggest that cytochrome P-450, particularly P-448 H, functions as the storage site of PenCDF in the rat liver.
Food and Cosmetics Toxicology | 1980
H. Kuroki; Y. Masuda; Shinichi Yoshihara; Hidetoshi Yoshimura
Abstract A mixture of polychlorinated dibenzofurans (PCDFs) was analysed by gas chromatography, mass fragmentography and high-pressure liquid chromatography. The mixture consisted of 14% 1,2,7,8-tetra-chlorodibenzofuran (1,2,7,8-tetra-CDF), 35% 2,3,7,8-tetra-, 1% 1,2,4,7,8-penta-, 49% 1,2,3,7,8-penta-, 1% 2,3,4,7,8-penta- and 1% hexa-CDF. The mixture was administered orally to monkeys and ip to rats. The livers of the animals were analysed for the individual PCDFs. It was found that the accumulative properties of the different PCDFs varied. 2,3,4,7,8-Penta-CDF was the most highly accumulative in the livers of both species.
Archives of Biochemistry and Biophysics | 1976
Kiyoshi Tatsumi; Shigeyuki Kitamura; Hidetoshi Yoshimura
Abstract An investigation was carried out to identify the reduction products of nitrofurazone and AF-2 (2-furyl)-3-(5-nitro-2-furyl)acrylamide by milk xanthine oxidase, rat liver xanthine oxidase, and rat liver microsomes. Data obtained from mass spectrometry and other methods indicated that the ethyl acetate-extractable major product of each nitrofuran derivative should be the corresponding amine derivative or the equivalent compound. This conclusion was further confirmed by an examination of stoichiometry. The reduced nitrofurazone was finally identified as 5-amino-2-furfural semicarbazone by comparative studies with the authentic specimen. The reduced AF-2 was tentatively identified as 2-(2-furyl)-3-(5-oxo-2-pyrrolin-2-yl)acrylamide. A reduction pathway for this conversion is postulated.
Xenobiotica | 1990
Kazuta Oguri; Nobumitsu Hanioka; Hidetoshi Yoshimura
1. Metabolites of codeine were determined by use of h.p.l.c. in urine of male mice, rats, guinea pigs and rabbits injected with 10 mg codeine/kg subcutaneously. 2. In 24 h urines of these species, unchanged codeine, codeine glucuronide, free morphine, and morphine-3-glucuronide were as follows: mice, 6.8, 1.6, 0.8 and 7.6% dose; rats, 1.6, 0.2, 4.3 and 23.9% dose; guinea pigs, 1.6, 39.8, 0.2 and 1.6% dose; rabbits, 2.2, 24.5, 1.3 and 17.9% dose. Urinary excretion of morphine-6-glucuronide was 0.7% dose in guinea pigs, 1.9% in rabbits, and not detectable in mice and rats. Norcodeine was found only in the urine of mice. 3. These results indicate that codeine is metabolized in all four species by glucuronidation and by oxidative N- and O-demethylation, but the quantitative excretions of metabolites were quite different in different species.
Xenobiotica | 1988
Takahiko Baba; Hideyuki Yamada; Kazuta Oguri; Hidetoshi Yoshimura
1. Five isozymes of cytochrome P-450 were purified from liver microsomes of phenobarbital-pretreated (P-450-SD-I and -II), 3-methylcholanthrene-pretreated (P-450-SD-III) and untreated rats (P-450-SD-IV and -V) to determine their catalytic activities in metabolic reactions of methamphetamine. 2. All the isozymes except P-450-SD-III showed considerably high N-hydroxylating activity of methamphetamine. The cytochromes P-450 initiate N-demethylation of this drug by two metabolic pathways, C-hydroxylation and N-hydroxylation. 3. Both N-demethylation and N-hydroxylation of methamphetamine were efficiently catalysed by the phenobarbital-inducible forms P-450-SD-I and -II and constitutive forms P-450-SD-IV and -V. 4. The constitutive forms P-450-SD-IV and -V revealed high catalytic activities of p-hydroxylation of methamphetamine, but phenobarbital- and 3-methylcholanthrene-inducible isozymes showed only low activities. 5. The present results indicate that the different extents of the metabolic intermediate complex formation with cytochrome P-450 (455 nm complex) in the microsomes from phenobarbital-, 3-methylcholanthrene-pretreated, and untreated rats is not attributable to the activities of the respective isozymes of cytochrome P-450 to form the precursor of the complex, N-hydroxymethamphetamine.